Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases

ABSTRACT

The present invention relates to novel antidiabetic compounds, their tautomeric forms, their derivatives, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. This invention particularly relates to novel azolidinedione derivatives of the general formula (I), and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them ##STR1##

This application is a continuation of Ser. No. 08/777,627 filed Dec. 31,1996 now U.S. Pat. No. 5,885,997, and a division of Ser. No. 08/884,816filed Jun. 30, 1997.

FIELD OF THE INVENTION

The present invention relates to novel antidiabetic compounds, theirtautomeric forms, their derivatives, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutically acceptablecompositions containing them. This invention particularly relates tonovel azolidinedione derivatives of the general formula (I), and theirpharmaceutically acceptable salts, pharmaceutically acceptable solvatesand pharmaceutical compositions containing them. ##STR2##

The present invention also relates to a process for the preparation ofthe above said novel, azolidinedione derivatives, their tautomericforms, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts, pharmaceutically acceptable solvates, novelintermediates and pharmaceutical compositions containing them.

The azolidinedione derivatives of the general formula (I) defined aboveof the present invention are useful for the treatment and/or prophylaxisof diseases Or conditions in which insulin resistance is the underlyingpathophysiological mechanism. Examples of these diseases and conditionsare type II diabetes, impaired glucose tolerance, dyslipidaemia,hypertension, coronary heart disease and other cardiovascular disordersincluding atherosclerosis. The azolidinedione derivatives of the formula(I) are useful for the treatment of insulin resistance associated withobesity and psoriasis. The azolidinedione derivatives of the formula (I)can also be used to treat diabetic complications and can be used fortreatment and/or prophylaxis of other diseases and conditions such aspolycystic ovarian syndrome (PCOS), certain renal diseases includingdiabetic nephropathy, glomerulonephritis, glomerular sclerosis,nephrotic syndrome, hypertensive nephrosclerosis, end-stage renaldiseases and microalbuminuria as well as certain eating disorders, asaldose reductase inhibitors and for improving cognitive functions indementia.

BACKGROUND OF THE INVENTION

Insulin resistance is the diminished ability of insulin to exert itsbiological action across a broad range of concentrations. In insulinresistance, the body secretes abnormally high amounts of insulin tocompensate for this defect; failing which, the plasma glucoseconcentration inevitably rises and develops into diabetes. Among thedeveloped countries, diabetes mellitus is a common problem and isassociated with a variety of abnormalities including obesity,hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75: 809-817: N.Engl. J. Med.; (1987) 317: 350-357; J. Clin. Endocrinol. Metab., (1988)66: 580-583; J. Clin. Invest., (1975) 68: 957-969) and other renalcomplications. (See Patent Application No. WO 95/21608). It is nowincreasingly being recognized that insulin resistance and relativehyperinsulinemia have a contributory role in obesity, hypertension,atherosclerosis and type 2 diabetes mellitus. The association of insulinresistance with obesity, hypertension and angina has been described as asyndrome having insulin resistance as the central pathogeniclink-Syndrome-X. In addition, polycystic ovarian syndrome (PatentApplication No. WO 95/07697), psoriasis (Patent Application No. WO95/35108). dementia (Behavioral Brain Research (1996) 75: 1-11) etc. mayalso have insulin resistance as a central pathogenic feature.

A number of molecular defects have been associated with insulinresistance. These include reduced expression of insulin receptors on theplasma membrane of insulin responsive cells and alterations in thesignal transduction pathways that become activated after insulin bindsto its receptor including glucose transport and glycogen synthesis.

Since defective insulin action is thought to be more important thanfailure of insulin secretion in the development of non-insulin dependentdiabetes mellitus and other related complications, this raises doubtsabout the intrinsic suitability of antidiabetic treatment that is basedentirely upon stimulation of insulin release. Recently, Takeda hasdeveloped a new class of compounds which are the derivatives of5-(4-alkoxybenzyl)-2,4-thiazolidinediones of the formula (II) (Ref Chem.Pharm. Bull. 1982, 30, 3580-3600). In the formula (II), V representssubstituted or unsubstituted divalent aromatic group and U representsvarious groups which have been reported in various patent documents.##STR3## By way of examples, U may represent the following groups:

(i) a group of the formula (IIa) where R¹ is hydrogen or hydrocarbonresidue or heterocyclic residue which may each be substituted, R² ishydrogen or a lower alkyl which may be substituted by hydroxy group, Xis an oxygen or sulphur atom, Z is a hydroxylated methylene or acarbonyl, m is 0 or 1, n is an integer of 1-3. These compounds have beendisclosed in the European Patent Application No. 0 177 353 ##STR4## Anexample of these compounds is shown in formula (IIb) ##STR5##

(ii) a group of the formula (IIc) wherein R¹ and R² are the same ordifferent and each represents hydrogen or C₁ -C₅ alkyl, R³ representshydrogen, acyl group, a (C₁ -C₆) alkoxycarbonyl group oraralkyloxycarbonyl group, R⁴ -R⁵ are same or different and eachrepresent hydrogen. C₁ -C₅ alkyl or C₁ -C₅ alkoxy or R⁴, R⁵ togetherrepresent C₁ -C₄ alkenedioxy group, n is 1, 2, or 3, W represents CH₂,CO, CHOR⁶ group in which R⁶ represents any one of the items or groupsdefined for R³ and may be the same or different from R³. These compoundsare disclosed in the European Patent Application No. 0 139 421. ##STR6##An example of these compounds is shown in (IId) ##STR7##

iii) A group of formula (IIe) where A¹ represents substituted orunsubstituted aromatic heterocyclic group. R¹ represents a hydrogenatom, alkyl group, acyl group, an aralkyl group wherein the aryl moietymay be substituted or unsubstituted, or a substituted or unsubstitutedaryl group, n represents an integer in the range from 2 to 6. Thesecompounds are disclosed in European Patent No. 0 306 228. ##STR8## Anexample of this compound is shown in formula (IIf) ##STR9##

iv) A group of formula (IIg) where Y represents N or CR⁵, R¹, R², R³, R⁴and R⁵ represents hydrogen, halogen, alkyl and the like and R⁶represents hydrogen, alkyl, aryl and the like, n represents an integerof 0 to 3. These compounds are disclosed in European Patent ApplicationNo. 0 604 983. ##STR10## An example of this compound is shown in formula(IIh) ##STR11##

Still another class of antihyperglycemic agents are 5-substitutedoxazolidine-2,4-diones and 2-substituted-1,2,4-oxadiazolidine-3,5-dioneswhich can be represented in the formula (IIi), ##STR12## where Vrepresents substituted or unsubstituted divalent aryl or hetero arylgroup, W represents various groups which have been reported in variouspatent documents, A represents nitrogen atom or a CH group and B is anoxygen atom.

By way of examples, W may represent the following groups:

v) a group of formula (IIj), where R is (C₁ -C₆) alkyl groups,cycloalkyl group, furyl, thienyl, substituted or unsubstituted phenylgroup, X is hydrogen, methyl methoxy, chloro or fluoro. These compoundshave been disclosed in the U.S. Pat. No. 5 037 842. ##STR13## An exampleof these compounds is shown in formula (IIk). ##STR14##

(vi) A group of formula (IIl) wherein A¹ represents a substituted orunsubstituted aromatic heterocyclyl group; R¹ represents a hydrogenatom, an alkyl group, an acyl group, an aralkyl group, wherein the arylmoiety may be substituted or unsubstituted or a substituted orunsubstituted aryl group, n represents an integer in the range of from 2to 6. These compounds have been disclosed in the patent application No.WO 92/02520. ##STR15## An example of these compounds is shown in formula(IIm). ##STR16##

(vii) A group of formulae (IIn) and (IIo), where R¹ is hydrogen, (C₁-C₈)alkyl, (C₁ -C₈)alkoxy, trifluoroalkoxy, halogen or trifluoromethylgroup, R² is hydrogen or methyl and X is oxygen or sulfur. Thesecompounds have been described in U.S. Pat. No. 5,480,486. ##STR17## Anexample of these compounds is shown in formula (IIp) ##STR18##

Some of the above referenced hitherto known antidiabetic compounds seemto possess bone marrow depression, liver and cardiac toxicities andmodest potency and consequently their regular use for the treatment andcontrol of diabetes is becoming limited and restricted.

SUMMARY OF THE INVENTION

With an objective of developing new compounds for the treatment of typeII diabetes [non-insulin-dependent-diabetes mellitus (NIDDM)] whichcould be more potent at relatively lower doses and having betterefficacy with lower toxicity, we focused our research efforts in adirection of incorporating safety and to have better efficacy, which hasresulted in the development of novel azolidinedione derivatives havingthe general formula (I) as defined above.

The main objective of the present invention is therefore, to providenovel azolidinedione derivatives, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates and pharmaceuticalcompositions containing them, or their mixtures.

Another objective of the present invention is to provide novelazolidinedione derivatives, their tautomeric forms, their stereoisomers,their polymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them or their mixtures having enhanced activities, no toxiceffect or reduced toxic effect.

Yet another objective of the present invention is to produce a processfor the preparation of novel azolidinediones of the formula (I) asdefined above, their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts and theirpharmaceutically acceptable solvates.

Still another objective of the present invention is to providepharmaceutical compositions containing compounds of the general formula(I), their tautomers, their stereoisomers, their polymorphs, theirsalts, solvates or their mixtures in combination with suitable carriers,solvents diluents and other media normally employed in preparing suchcompositions.

Yet another objective of the present invention is to provide a processfor the preparation of the novel intermediate of the formula (III)##STR19## where G represents --CHO, --NO₂, --NH₂, --CH═NHOH, --CH₂ NHOH,--CH₂ N(OH)CONH₂ or --CH₂ CH(J)-COOR, where J represents hydroxy group,halogen atom such as chlorine, bromine or iodine and R represents H orlower alkyl group such as methyl, ethyl, or propyl, X, Y, Z, R¹, R², R³,n, and Ar are defined as in formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Azolidinedione derivatives of the present invention have the generalformula (I) ##STR20##

In the above formula (I), one of X, Y or Z represents C═O or C═S and theremaining of X, Y and Z represent a group C═ or C═C, R¹, R² and R³ aregroups either on X, Y or Z or on a nitrogen atom R¹, R² and R³ may besame or different and represent hydrogen, halogen, hydroxy, or nitro, oroptionally substituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl,acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl,aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkylgroups, carboxylic acid or its derivatives, or sulfonic acid or itsderivatives with the provision that when R¹, R² or R³ is on a nitrogenatom it does not represent hydrogen, halogen, nitro, carboxylic acid orsulfonic acid groups, or any two of R¹, R² and R³ along with theadjacent atoms to which they are attached may also form a substituted orunsubstituted cyclic structure of from 4 to 7 atoms with one or moredouble bonds, the cyclic structure may be carbocyclic or may contain oneor more heteroatoms selected from oxygen nitrogen and sulfur. When thegroups representing R¹, R² or R³ are substituted, the substituents areselected from the same groups that may represent R¹, R², and R³ such ashydroxy, halogen, or nitro, or optionally substituted groups selectedfrom alkyl, cycloalkyl alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino,acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino,alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives. The linking grouprepresented by --(CH₂)_(n) --O-- in formula (I) may be attached eitherthrough nitrogen atom or through X, Y or Z where n is an integer rangingfrom 1-4. Ar represents an optionally substituted divalent aromatic orheterocyclic group, R⁴ represents hydrogen atom, halogen or lower alkylgroup or forms a bond together with the adjacent group A. A represents anitrogen atom or a group CR⁵ where R⁵ represents hydrogen, halogen orlower alkyl group such as methyl ethyl, propyl or the like or R⁵ forms abond together with R⁴ ; B represents an oxygen atom or a sulfur atomwhen A is CR⁵ and B represents an oxygen atom when A is a nitrogen atom.

Suitable combinations of X, Y and Z that form the ring structurecontaining X, Y and Z in the formula (I) are represented in thefollowing Table:

    ______________________________________                                        S. No.   X           Y           Z                                            ______________________________________                                        1.       C═ O or C═ S                                                                      ═ C     C═ C                                       2.      C═ O or C═ S       C═ C                ═ C                                            3.      ═ C               C═ O                                       or C═ S       C═ C                     4.      ═ C               C═ C            C═ O or C═ S                                        5.       C═ C              C═ O                                      or C═ S     ═ C                        6.    C═ C              ═ C             C═ O or C═          ______________________________________                                                                         S                                        

It is preferred that at least one of X, Y or Z be C═C.

It is preferred that one of X or Y be C═O. Suitable ring structurescontaining X, Y and Z include ##STR21##

A preferred ring structure is ##STR22##

When R¹, R² and R³ groups are attached to X, Y, and Z it is preferredthat R¹, R² and R³ are selected from hydrogen, halogen atom such asfluorine, chlorine, bromine, or iodine; hydroxy, nitro; substituted orunsubstituted (C₁ -C₁₂)alkyl group, especially, linear or branched (C₁-C₆)alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, t-butyl and the like; cycloalkyl group such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like; cycloalkyloxy groupsuch as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy andthe like; aryl group such as phenyl or naphthyl, the aryl group may besubstituted; aralkyl such as benzyl or phenethyl, the aralkyl group maybe substituted; heteroaryl group such as pyridyl, thienyl, furyl,pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl, benzopyranyl,benzofuranyl and the like, the heteroaryl group may be substituted;heterocyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl,piperidinyl and the like, the heterocyclyl group may be substituted;aryloxy such as phenoxy, naphthyloxy, the aryloxy group may besubstituted; alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl;aryloxycarbonyl group such as optionally substituted phenoxycarbonyl;arylamino group such as HNC₆ H₅ ; amino group; amino(C₁ -C₆)alkyl;hydroxy(C₁ -C₆)alkyl; (C₁ -C₆)alkoxy; thio(C₁ -C₆)alkyl; (C₁-C₆)alkylthio; acyl group such as acetyl, propionyl or benzoyl, the acylgroup may be substituted; acylamino groups such as NHCOCH₃, NHCOC₂ H₅,NHCOC₃ H₇, NHCOC₆ H₅, aralkoxycarbonylamino group such as NHCOOCH₂ C₆H₅, alkoxycarbonylamino group such as NHCOOC₂ H₅, NHCOOCH₃ and the like;carboxylic acid or its derivatives such as amides, like CONH₂, CONHMe,CONMe₂, CONHEt, CONEt₂, CONHPh and the like, the carboxylic acidderivatives may be substituted; acyloxy group such as OCOMe, OCOEt,OCOPh and the like which may optionally be substituted; sulfonic acid orits derivatives such as SO₂ NH₂, SO₂ NHMe, SO₂ NMe₂, SO₂ NHCF₃ and thelike; the sulfonic acid derivatives may be substituted.

All of the preferred groups that may represent R¹, R² and R³ may besubstituted or unsubstituted.

When R¹, R² or R³ are attached to nitrogen atom, it is preferred thatR¹, R² and R³ are selected from (C₁ -C₁₂)alkyl group, especially linearor branched (C₁ -C₆)alkyl group, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, t-butyl groups and the like; cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike; aryl group such as phenyl or naphthyl; aralkyl such as benzyl orphenethyl; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl,oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl and the like; heterocyclylgroups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl andthe like; alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl;aryloxycarbonyl group such as phenoxycarbonyl; amino(C₁ -C₆)alkyl;hydroxy(C₁ -C₆)alkyl; thio(C₁ -C₆)alkyl; or acyl group such as acetyl,propionyl, benzoyl, and the like.

All of the preferred groups that may represent R¹, R² and R³ may besubstituted or unsubstituted.

When the groups represented by R¹, R² and R³ are substituted, thesubstituents selected are from the same groups as those groups thatrepresent R¹, R² and R³ and may be selected from halogen, hydroxy, ornitro, or optionally substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl,heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino,aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio,thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acidor its derivatives.

Suitable ring structure formed by any two of R¹, R² and R³ along withthe adjacent atoms to which they are attached, include substituted orunsubstituted 4 -7 membered cyclic structure which may contain one ormore double bonds, the cyclic structure may be carbocyclic or optionallycontains one or more hetero atoms selected from nitrogen, oxygen andsulfur. Examples of the cyclic structures are phenyl, naphthyl, thienyl,furyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl,azacyclobutenyl, isoxazolyl, azepinyl, pyridyl, pyridazyl, pyrimidinyl,dihydrofuryl, dihydrothienyl, tetrahydropyridyl, tetrahydrophenyl,tetrahydronaphthyl and the like. The substituents on the cyclicstructure may be selected from the same groups as that of R¹, R² and R³.Examples of possible substituents are halogen, alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl,heteroaralkyl, hydroxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino,arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl,carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

It is more preferred that R¹, R² and R³ groups represent hydrogen;halogen atom such as fluorine, chlorine, bromine, or iodine; alkyl groupsuch as methyl, ethyl, n-propyl or n-butyl; cycloalkyl group such ascyclopropyl; aryl group such as phenyl; or aralkyl group such as benzyl.

When the groups represented by R¹, R² and R³ are substituted it ispreferred that the substituents are selected from halogen, haloalkyl,haloalkoxy, and halocycloalkoxy wherein the halogen atom is preferably afluorine atom.

The ring structure formed by any two of R¹, R² and R³ along with theadjacent atoms to which they are attached, may be substituted orunsubstituted. Preferred ring structures are phenyl, thienyl, furyl orpyridyl groups. When these ring structures are substituted it ispreferred that the substituents are selected from halogen, lower alkylgroup such as methyl or ethyl; trifluoromethyl; fluoromethyl;difluoromethyl; and alkoxy groups such as methoxy, trifluoromethoxy,fluoromethoxy and difluoromethoxy.

The linking group --(CH₂)_(n) --O-- may be linked either through anitrogen atom or through X, Y or Z. The integer n may range from 1 to 4,preferably n is 1 to 2. It is preferred that the king group be linkedeither through nitrogen or through Z when Z represents ═C.

It is preferred that the group represented by Ar be substituted orunsubstituted divalent phenylene, naphthylene, pyridyl, quinolinyl,benzofuryl, dihydrobenzofuryl, benzopyranyl, indolyl, indolinyl,azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl andthe like. The substituents on the group represented by Ar may beselected from linear or branched (C₁ -C₆)alkyl, (C₁ -C₃)alkoxy, halogen,acyl, amino, acylamino, thio, or carboxylic or sulfonic acids or theirderivatives.

It is more preferred that Ar represents substituted or unsubstituteddivalent phenylene, naphthylene, benzofuryl, indolinyl, quinolinyl,azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl.

It is still more preferred that Ar is represented by divalent phenyleneor naphthylene, which may be optionally substituted by methyl,halomethyl, methoxy or halomethoxy groups.

Suitable R⁴ includes hydrogen; lower alkyl group such as methyl ethyl orpropyl; halogen atom such as fluorine, chlorine, bromine or iodine, orR⁴ together with A represents a bond.

Suitable A group may be nitrogen or CR⁵ where R⁵ may be a hydrogen atom,halogen, lower alkyl group or together with R⁴ forms a bond.

Suitable B group includes a hetero atom selected from O or S, with theprovision that when A is CR⁵, B is selected from sulfur or oxygen, andwhen A is nitrogen, B represents oxygen

Suitable ring structure comprising A and B include2,4-dioxooxazolidin-5-yl, 2,4-dioxooxazolidin-5-yl,3,5-dioxol,2,4-oxadiazolidin-2-yl groups. Preferred ring structurescomprising, A and B include 2,4-dioxooxazolidine-5-yl and2,4-dioxothiazolidin-5-yl groups.

It is more preferred that the ring structure comprising A and B is a2,4-dioxothiazolidin-5-yl group.

Pharmaceutically acceptable salts forming part of this invention includesalts of the azolidinedione moiety such as alkali metal salts like Li,Na, and K salts, alkaline earth metal salts like Ca and Mg salts, saltsof organic bases such as lysine, arginine, guanidine, diethanolamine,choline and the like, ammonium or substituted ammonium salts, salts ofcarboxy group wherever appropriate, such as aluminum, alkali metalsalts; alkaline earth metal salts, ammonium or substituted ammoniumsalts. Salts may include acid addition salts which are, sulphates,nitrates, phosphates, perchlorates, borates, hydrohalides, acetates,tartrates, maleates, citrates, succinates, palmoates, methanesulfonates,benzoates, salicylates, hydroxynaphthoates, benzenesulfonates,ascorbates, glycerophosphates, ketoglutarates and the like.Pharmaceutically acceptable solvates may be hydrates or comprising othersolvents of crystallization such as alcohols.

Particularly useful compounds according to the present inventionincludes:

5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione and its salts,

5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4 dione and its salts,

5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione and its salts,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione and its salts and its polymorphs,

5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione and its salts,

5-[4-[2-[6,7-dimethoxy-2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]oxazolidine-2,4-dione and its salts,

5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]oxazolidine-2,4-dione and its salts,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]oxazolidine-2,4-dione and its salts,

2-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]-1,2,4 oxadiazolidine-3,5-dione and its salts,

2-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]-1,2,4-oxadiazolidine-3,5-dione and its salts,

2-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]-1,2,4-oxadiazolidine-3,5-dione and its salts,

5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione and its salts,

5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione and its salts,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethylene]thiazolidine-2,4-dione and its salts,

5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethylene]thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione and its salts,

5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione and its salts,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-3-methoxyphenylmethylene]thiazolidine-2,4-dione and its salts,

More preferred compounds according to the present invention include

5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione,

5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine 2,4-dione,

5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione, sodium salt,

5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione, sodium salt.

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione and its polymorphs,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione sodium salt and its polymorphs,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione, potassium salt,

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethylene]thiazolidine-2,4-dione, sodium salt.

According to a feature of the present invention, there is provided aprocess for the preparation of novel intermediate of the general formula(III) ##STR23## where X, Y, Z, R¹, R², R³ and n are as defined earlier,-(CH₂)_(n) --O-- linker is attached to nitrogen atom, G represents --CHOor --NO₂ group which comprises, reacting a compound of the generalformula (IV) ##STR24## where X, Y, Z, R¹, R² and R³ are as definedearlier and H atom is attached to one of the nitrogen atoms of the ring,with a compound of general formula (V) ##STR25## where Ar and n are asdefined earlier and L¹ may be a halogen atom such as Cl, Br, I or aleaving group such as methanesulfonate, trifluoromethanesulfonate,p-toluenesulfonate etc, and G represents CHO, or NO₂ group.

The reaction of a compound of general formula (IV) with a compound ofgeneral formula (V) to produce a compound of general formula (III) maybe carried Out in the presence of solvents such as DMSO, DMF, DME, THF,dioxane, ether and the like or a combination thereof The reaction may becarried out in an inert atmosphere which may be maintained by usinginert gases such as N₂, Ar, He. The reaction may be effected in thepresence of a base such as alkalis like sodium hydroxide, potassiumhydroxide, alkali metal carbonates like sodium carbonate potassiumcarbonate; alkali metal hydrides such as sodium hydride or potassiumhydride; organometallic bases like n-butyl lithium, alkali metal amideslike sodamide or mixtures thereof The amount of base may range from 1 to5 equivalents, based on the amount of the compound of formula (IV).preferably the amount of base ranges from 1 to 3 equivalents. 1 to 3equivalents of alkali metal halides based on the amount of compound offormula (IV) such as lithium bromide may be added as an additive. Thereaction may be carried out at a temperature in the range of 0° C. to150° C., preferably at a temperature in the range of 15° C. to 100° C.The duration of the reaction may range from 0.25 to 24 hours, preferablyfrom 0.25 to 6 hours.

In another embodiment of the invention, the novel intermediate of thegeneral formula (III) defined and obtained above where G is CHO or NO₂group, can be prepared by reacting the compound of the general formula(VI). ##STR26## wherein, X, Y, Z, R¹, R², R³ and n are as definedearlier, with a compound of general formula (VII) ##STR27## where L² isa halogen atom. G is a CHO or a NO₂ group and Ar is as defined earlier.

The reaction of compound of formula (VI) with the compound of formula(VII) to produce a compound of formula (III) may be carried out in thepresence of solvents such as THF, DMF, DMSO, DME and the like. The inertatmosphere may be maintained by using inert gases such as N₂, Ar or He.The reaction may be effected in the presence of a base such as K₂ CO₃,Na₂ CO₃, NaH. The reaction temperature may range from 20° C. to 150° C.,preferably at a temperature in the range of 30° C. to 100° C. Theduration of the reaction may range from 1 to 24 hours, preferably from 2to 6 hours.

In another embodiment of the present invention, the novel intermediateof general formula (III), where G is a CHO or NO₂ group, can also beprepared by the reaction of compound of general formula (VIII) ##STR28##where X, Y, Z, R¹, R², R³, n and L¹ are as defined earlier with acompound of general formula (IX) ##STR29## where G is a CHO or NO₂ groupand Ar is as defined earlier.

The reaction of compound of formula (VIII) with compound of formula (IX)to produce a compound of the formula (III) may be carried out in thepresence of solvents such as THF. DMF DMSO, DME and the like or mixturesthereof The reaction may be carried out in an inert atmosphere which maybe maintained by using inert gases such as N₂, Ar, or He. The reactionmay be effected in the presence of a base such as K₂ CO₃, Na₂ CO₃ or NaHor mixtures thereof The reaction temperature may range from 20° C.-120°C., preferably at a temperature in the range of 30° C.-100° C. Theduration of the reaction may range from 1 to 12 hours, preferably from 2to 6 hours.

The present invention provides a process for the preparation of novelazolidinedione derivatives of general formula (I), their tautomericforms, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts and their pharmaceutically acceptable solvates whereinR¹, R², R³, X, Y, Z, n and Ar are as defined earlier and A representsCR⁵ where R⁵ together with R⁴ represent a bond and B represents a sulfuror a oxygen atom, and further to a compound of formula (I) wherein R⁴and R⁵ represent hydrogen and all symbols are as defined above, whichcomprises:

reacting the novel intermediate of the general formula (III) obtainedabove where G represents CHO group with 2,4-thiazolidinedione or2,4-oxazolidinedione and removing the water formed during the reactionby conventional methods to yield a compound of general formula (X)##STR30## where R¹, R², R³, X, Y, Z, n and Ar are as defined earlier andB represents sulfur or oxygen.

The reaction between the compound of the general formula (III) where Gis a CHO group with 2,4-thiazolidinedione or 2,4-oxazolidinedione, toyield compound of general formula (X) wherein B represents a sulfur oran oxygen atom respectively, may be carried out neat in the presence ofsodium acetate or in the presence of a solvent such as benzene, toluene,methoxyethanol or mixtures thereof The reaction temperature may rangefrom 80° C. to 140° C. depending upon the solvents employed and in therange from 80° C. to 180° C. when the reaction is carried out neat inthe presence of sodium acetate. Suitable catalyst such as piperidiniumacetate or benzoate, sodium acetate or mixtures of catalysts may also beemployed. Sodium acetate can be used in the presence of solvent, but itis preferred that sodium acetate is used neat. The water produced in thereaction may be removed, for example, by using Dean Stark waterseparator or by using water absorbing agents like molecular seives.Oxazolidine-2-oxo-4-thione may be used instead of 2,4-oxazolidinedione.However, the thio group needs to be converted to oxo group by oxidationusing agents such as hydrogen peroxide or peroxyacids like mCPBA.

The compound of the general formula (X) obtained in the manner describedabove is reduced by known method to obtain the compound of generalformula (XI) ##STR31## wherein R¹, R², R³, X, Y, Z, n and Ar are asdefined earlier and B represents a sulfur atom or an oxygen atom. Thecompound of general formula (XI) represents the compound of generalformula (I). wherein R⁴ is hydrogen, A is CR⁵ where R⁵ is hydrogen andother symbols are as defined earlier.

The reduction of compound of the formula (X) to yield a compound of thegeneral formula (XI) may be carried out in the presence of gaseoushydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the like. Mixturesof catalysts may be used. The reaction may also be conducted in thepresence of solvents such as dioxane, acetic acid, ethyl acetate and thelike. A pressure between atmospheric pressure and 80 psi may beemployed. The catalyst may be 5-10% Pd/C and the amount of catalyst usedmay range from 50-300% w/w. The reaction may also be carried out byemploying metal solvent reduction such as magnesium in methanol orsodium amalgam in methanol.

The compound of the general formula (XI) obtained above is convertedinto its pharmaceutically acceptable salts, or its pharmaceuticallyacceptable solvates by conventional methods.

In another embodiment of the present invention, the compound of thegeneral formula (I) can also be prepared by reacting a compound of thegeneral formula (VIII) defined above with a compound of general formula(XII) ##STR32## where R⁴, A, B and Ar are as defined earlier and R⁶ ishydrogen or a nitrogen protecting group which is removed after thereaction.

The reaction of compound of formula (VIII) with compound of formula(XII) to produce a compound of the formula (I) may be carried out in thepresence of solvents such as THF, DMF, DMSO, DME and the like ormixtures thereof. The reaction may be carried out in an inert atmospherewhich is maintained by using inert gases such as N₂, Ar or He. Thereaction may be effected in the presence of a base such as K₂ CO₃, Na₂CO₃ or NaH or mixtures thereof. The reaction temperature may range from20° C.-120° C., preferably at a temperature in the range of 30° C.-80°C. The duration of the reaction may range from 1 to 12 hours, preferablyfrom 2 to 6 hours.

In still another embodiment of the invention, the compound of thegeneral formula (I), where --(CH₂)_(n) --O-- linker is attached tonitrogen atom can be prepared by reacting the compound of the generalformula (IV) defined above with a compound of general formula (XIII)##STR33## where L¹, n, Ar, A, B, R⁴ and R⁶ are as defined earlier andremoval of the protecting group when R⁶ is a nitrogen protecting group.

The reaction of compound of general formula (IV) with a compound ofgeneral formula (XIII) to produce a compound of general formula (I) maybe carried out in the presence of solvents such as THF, DMF, DMSO, DMEand the like or mixtures thereof. The reaction may be carried out in aninert atmosphere which is maintained by using inert gases such as N₂, Aror He. The reaction may be effected in the presence of a base such asalkalis like sodium hydroxide, or potassium hydroxide; alkali metalcarbonates like sodium carbonate, or potassium carbonate: alkali metalhydrides such as sodium hydride: organometallic bases like n-butyllithium: alkali metal amides like sodamide, or mixtures thereof Multiplesolvents and bases can be used. The amount of base may range from 1 to 5equivalents, preferably 1 to 3 equivalents. 1 to 3 equivalents of alkalimetal halides such as lithium bromide may be added as an additive. Thereaction temperature may be in the range of 0° C. to 120° C., preferablyat a temperature in the range of 20° C. to 100° C. The duration of thereaction may range from 0.5 to 24 hours, preferably from 0.5 to 6 hours.

In yet another embodiment of the present invention, the compound ofgeneral formula (I), where R¹, R², R³, X, Y, Z, n and Ar are as definedearlier, R⁴ represents hydrogen and A is CH and B represents S or O canbe prepared by the reaction of compound of general formula (XIV)##STR34## where R¹, R², R³, X, Y, Z, n and Ar are as defined earlier, Jis a halogen atom like chlorine, bromine or iodine or a hydroxy groupand R is a lower alkyl group, with urea when J is a OH group and withthiourea when J is a halogen atom, followed by treatment with an acid.

The reaction of compound of general formula (XIV) with urea or thioureais normally carried out in the presence of alcoholic solvent such asmethanol, ethanol, propanol, isobutanol, 2-methoxybutanol, etc or DMSOor sulfolane. The reaction may be conducted at a temperature in therange between 20° C. and the reflux temperature of the solvent used.Bases such as NaOAc, KOAc, NaOMe, NaOEt etc. can be used. The reactionis normally followed by treatment with a mineral acid such ashydrochloric acid at 20° C. to 100° C.

The compound of general formula (XIV) where J is hydroxy group isprepared by the hydrolysis of compound of general formula (XIV) where Jis a halogen atom using aqueous alkali at a temperature ranging from 20°C. to 100° C. followed by reesterification of the hydrolysed acid groupby conventional methods.

The compound of general formula (XIV) where J is a OH group may also beprepared from compound of formula (XIV) where J is a halogen atom byreacting with formamide in the presence of water. The amount offormamide used in the reaction ranges from 0.5 to 1.5 mL and water usedranges from 20 μL to 0.1 mL for one mmol of the halo compound (XIV). Thereaction is conducted at a temperature ranging from 80° C. to 180° C.,preferably from 120° C. to 150° C., over a period ranging from 1 to 8hours.

The compound of general formula (XIV) where J is a halogen atom can beprepared by the diazotization of the amino compound of the generalformula (XV) ##STR35## where all symbols are as defined earlier, usingalkali metal nitrites followed by treatment with acrylic acid esters inthe presence of hydrohalo acids and catalytic amount of copper oxide orcopper halide.

The compound of general formula (XV) can in turn be prepared by theconventional reduction of the novel intermediate (III) where G is NO₂group and other symbols are as defined earlier.

In another embodiment of the present invention, the compound of generalformula (I), where R¹, R², R³, X, Y, Z, n and Ar are as defined earlierand A is nitrogen atom and B is oxygen atom can be prepared by a processwhich comprises: reaction of novel intermediate of formula (III) whereall symbols are as defined above, and G represents a CHO group with NH₂OH. HCl to yield a compound of general formula (III) where G representsCH═NOH group and all symbols are as defined earlier, followed by metalborohydride reduction to yield a compound of general formula (XVI)##STR36## where all symbols are as defined earlier.

The reaction of compound of general formula (III), where G is CHO groupand other symbols are as defined earlier, with hydroxylaminehydrochloride is carried out in solvents such as ethanol, methanol, THF,dioxane and the like following the conventional method to make oximes. 1to 10 equivalents of NH₂ OH.HCl may be used, preferably, 2 to 5equivalents. Bases such as alkali metal acetates or ammonium acetate maybe used. Reaction may be carried out in the presence of water.Temperature in the range of 0° C. to reflux temperature of the solventmay be used. The oxime obtained in the manner described above is reducedusing reducing agents such as alkali metal borohydrides like sodiumborohydride or sodium cyanoborohydride or borane reagents usingconventional conditions to yield the compound of general formula (XVI).

The compound of general formula (XVI) in turn is reacted withhalocarbonyl isocyanate or alkoxycarbonyl isocyanate to yield a compoundof general formula (I) or with KOCN to yield a compound of generalformula (III) where G is CH₂ N(OH)CONH₂, followed by treatment withcarbonylating agents such as alkyl haloformate to produce the compoundof general formula (I) where R¹, R², R³, X, Y, Z, n, Ar are as definedearlier, A represents nitrogen atom and B is oxygen atom.

The reaction of compound of general formula (XVI) with halocarbonylisocyanate such as chlorocarbonyl isocyanate or alkoxycarbonylisocyanate such as ethoxycarbonyl isocyanate may be carried out in inertsolvents such as THF, dioxane, etc at a temperature in the range -15° C.to 50° C. The reaction may be carried out for 0.5 to 12 hours dependingon the substrates used for the reaction.

Alternatively, the compound of general formula (XVI) may be treated withexcess of KOCN hi organic acids such as acetic acid. Water may be usedin the reaction. The reaction may be carried out at a temperature in therange of 20° C. to 120° C. The product isolated in the reaction isfurther treated with alkyl haloformate such as ethyl chloroformate inthe presence of 1 to 10 equivalents of alkali such as sodium hydroxide,potassium hydroxide and the like to obtain compound of general formula(I) where all the symbols are as defined earlier and A representsnitogen atom and B represents oxygen atom.

In yet another embodiment of the invention, the compound of generalformula (I), where the linker --(CH₂)_(n) --O-- is attached through Z,where Z represents ═C, and all other symbols are as defined earlier canbe prepared by reacting the compound of general formula (XVII) ##STR37##where R¹, R², and R³ are as defined earlier, X represents C═O or C═S andY represents C═C; or when R² and R³ together with Y form a cyclicstructure as defined earlier. X represents C═O or C═S, Y represents C═Cand R¹ is as defined earlier, with a compound of general formula (XVIII)##STR38## where Ar, R⁴, A, B and n are as defined earlier, D may be--CN; --C(OR⁷)₃ where R⁷ is (C₁ -C₄)alkyl; --C(═O)--R⁸ where R⁸ may beselected from --OH, Cl, Br, I, --NH₂, --NHR, OR where R is a lower alkylgroup such as methyl, ethyl, propyl and the like, or R⁸ may beO--(C═O)--R⁹, where R⁹ may be a linear or branched (C₁ -C₅)alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like,2,4-dichlorophenyl, 2,4,6-trichlorophenyl groups. The reaction proceedsthrough the intermediate formation of compound of general formula (XIX).##STR39## where all symbols R¹, R², R³, R⁴, X, Y, A, B, Ar and n are asdefined earlier.

The group X--NHR¹ in formula (XIX) can also be generated by conventionalmethods such as amidation of an ester group (XOR) or partial hydrolysisof a CN (in a compound where CN group is present in the place ofX--NHR¹) group.

The reaction of compound of general formula (XVII) with a compound ofgeneral formula (XVIII) to produce a compound of general formula (I) maybe carried out in neat or in the presence of solvents such as xylene,toluene, THF, dioxane, acetic acid, DMF, DMSO and the like or mixturesthereof. The reaction may be carried out in an inert atmosphere whichmay be maintained by using inert gases such as N₂, Ar or He. Thereaction may be carried out at a temperature in the range of 50° C. to200° C., preferably at a temperature in the range of 60° C. to 180° C.The reaction may be effected in the presence or in absence of a base oran acid. The nature of the base or the acid is not critical. Example ofsuch bases include organic bases such as pyridine, lutidine, triethylamine, diisopropylethyl amine and the like, metal carbonates such as K₂CO₃, Na₂ CO₃. Examples of acids include organic acids such as AcOH, C₂H₅ COOH, butyric acid, p-toluenesulfonic acid, benzenesulfonic acid andthe like, mineral acids such as HCl, HBr etc. The duration of thereaction may range from 0.25 to 48 hours, preferably from 0.50 to 18hours.

Alternatively, the novel intermediate of formula (XIX) may be isolatedand then cyclised to yield a compound of formula (I).

The reaction of compound of the formula (XVII) with a compound offormula (XVIII) to yield a compound of the formula (XIX) may be carriedout neat or in presence of solvent such as xylene, toluene, dioxane,DMF, DMSO, halogenated hydrocarbons such as CH₂ Cl₂, CHCl₃, ClCH₂ CH₂ Cland the like or mixtures thereof. The reaction may be effected hi thepresence or absence of a base or an acid. The nature of the base or acidis not critical. Examples of such bases include organic bases such aspyridine, lutidine, triethyl amine, diisopropylethyl amine and the like.Examples of acids used for this reaction includes CH₃ COOH, C₂ H₅ COOH,butyric acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.The reaction may be carried out in au inert atmosphere which may bemaintained by using inert gases such as N₂, Ar or He. The reaction maybe carried out at a temperature in the range of 25° C. to 180° C.,preferably in the range of 25° C. to 100° C. The reaction is generallyinstantaneous and the duration of the reaction may range from 0.25 to 24h, preferably 0.25 to 2 h.

The cyclisation of the compound of formula (XIX) to yield a compound ofthe formula (I) may be carried out neat or in the presence of solventssuch as THF, toluene, xylene, 1,4-dioxane and the like or mixturesthereof The reaction temperature may range from 60° C. to 150° C.depending upon the solvent employed and in the range from 100° C. to200° C. when the reaction is carried out neat. The reaction may beeffected in presence or absence of acids. The acids normally usedinclude acetic acid, propionic acid, butyric acid, pTsOH and the like.The amount of acid used may range from 0.1 to 100 equivalents,preferably 0.1 to 10 equivalents. The reaction can also be carried outin neat acid. The reaction is preferably carried out in solvents such asTHF, toluene, xylene, 1,4-dioxane or mixtures thereof in the presence ofail acid such as acetic acid, propionic acid, p-TsOH and the like. Theduration of the reaction may range from 3 to 48 h preferably from 4 to18 h.

The process described in the above embodiment is novel and unique sincethe heterocycle has been built in the final step of the process. In thepresent process no side products are observed. The yields are high andno purification is required for any intermediate involved. The processdescribed in the above embodiment does not involve any stringentconditions This process works well for both small scale and large scalereactions. The process described in the above embodiment is preferablyused for compounds of formula (I) wherein R² and R³ together form acyclic structure as defined earlier with Y, wherein Y represents C═C.

The compound of general formula (XVIII) where D represents --COOH andall other symbols are as defined earlier is prepared from the compoundof general formula (XVIII) where D represents --COOR where R is a loweralgal group such as CH₃, C₂ H₅, C₃ H₇ and all other symbols are asdefined earlier by conventional hydrolysis procedures.

The hydrolysis of the compound of formula (XVIII) where D representsCOOR group to yield a compound of the formula (XVIII) where D representsCOOH group, may be carried out in the presence of solvents such asmethanol, ethanol, dioxane, ether, THF, water and the like or mixturesthereof. The reaction may be effected in the presence of a base such asan alkali like NaOH, KOH or alkali metal carbonates like sodiumcarbonate, potassium carbonate and the like. The amount of base mayrange from 1 to 5 equivalents. The reaction may be carried out at atemperature in the range of 0° C. to 120° C., preferably at atemperature in the range of 15° C. to 100° C. The duration of thereaction may range from 0.25 to 24 h, preferably from 0.5 to 5 h.

The compound of general formula (XVIII) where D represents COCl or COBrand other symbols are as defined earlier may be prepared by the reactionof compound of general formula (XVIII) where D represents COOH and othersymbols are as defined earlier with reagents such as SOCl₂, PCl₃, PCl₅,PBr₃ and the like. The reaction may be carried out neat or in thepresence of solvents such as benzene, xylene etc. The reaction may becarried out in the range of 0° C. to 140° C. preferably in the range of25° C. to 100° C. The duration of the reaction may range from 0.25 to 24h, preferably 0.5 to 5 h.

The compound of general formula (XVIII) where all symbols are as definedearlier and D represents --C(═O)--O--(C═O)--R⁹, where R⁹ represents alinear or branched (C₁ -C₅) alkyl group, dichlorophenyl, trichlorophenylgroup and the like, may be prepared by the reaction of compound ofgeneral formula (XVIII) where D represents COOH and all other symbolsare as defined earlier, with organic acid halides such as acetylchloride, acetyl bromide, propanoyl chloride, butanoyl chloride,pivaloyl chloride, trichlorobenzoylchloride and the like in the presenceof a base such as pyridine, N,N-dimethylaminopyridine, triethyl amine,diisopropylethyl amine, lutidine and the like or a mixture thereof. Thereaction may be carried out in solvents such as CH₂ Cl₂, CHCl₃, ClCH₂CH₂ Cl, 1,4-dioxane, xylene and the like. The reaction may be carriedout at a temperature in the range of 0° C. to 120° C., preferably in therange of 0° C. to 50° C. The duration of the reaction may range from0.25 to 12 h, preferably 0.5 to 5 h.

Particularly useful compound of general formula (I) where X representsC═O, Y represents C═C, Z represents ═C, n represents an integer 1, R¹represents methyl group, B represents sulfur atom, R² and R³ togetherwith Y form a phenyl ring represented by formula (XX) can be preparedaccording to the process described in the above embodiment comprising:##STR40##

a) Reducing a compound of formula (XXI) which is disclosed in JP 2558473##STR41## where R¹⁰ is a lower alkyl group such as methyl, ethyl and thelike using conventional reduction conditions to yield a compound offormula (XXII) ##STR42## where R¹⁰ is as defined above.

The reduction of compound of the formula (XXI) to yield a compound ofthe formula (XXII) may be carried out in the presence of gaseoushydrogen and a catalyst such as Pd/C or Raney nickel. Mixtures ofcatalysts may be used. Solvents such as dioxane, acetic acid ethylacetate and the like may be used. A pressure between atmosphericpressure and 80 psi may be employed. The catalyst may be 5-10% Pd/C andthe amount of catalyst used may range from 50-300% w/w. The reaction mayalso be carried out by employing metal solvent reduction such asmagnesium in methanol or sodium amalgam in methanol.

b) Hydrolysis of compound of formula (XXII) using conventionalconditions to yield a compound of formula (XXIII) ##STR43##

The hydrolysis of the compound of formula (XXII) to yield a compound ofthe formula (XXIII) may be carried out in the presence of solvents suchas methanol, ethanol, dioxane, ether, THF, water and the like ormixtures thereof. The reaction may be effected in the presence of a basesuch as alkali like NaOH, KOH, alkali metal carbonates like sodiumcarbonate and potassium carbonate. The amount of base may range from 1to 5 equivalents, based on the amount of the compound of formula (XXII).The reaction may be carried out at a temperature in the range of 0° C.to 120° C., preferably at a temperature in the range of 15° C. to 100°C. The duration of the reaction may range from 0.25 to 24 h, preferablyfrom 0.5 to 5 h.

c) Reacting a compound of formula (XXIII) with acid halide orhalogenating agent to obtain a compound of formula (XXIV), ##STR44##where D represents COCl or COBr or --C(═O)--O--(C═O)--R⁹, where R⁹represents methyl or t-butyl group.

The reaction of compound of formula (XXIII) with halogenating agent suchas SOCl₂, PCl₅, PBr₃ may be carried out neat or in presence of solventsuch as benzene, xylene etc. The reaction may be carried out at 0° C. to140° C., preferably at 25° C. to 100° C. The duration of the reactionmay range from 0.25 to 24 h, preferably 0.5 to 5 h. The reaction ofcompound of formula (XXIII) with acid halide to yield mixed anhydride,may be carried out with acid halides such as acetyl chloride or pivaloylchloride in the presence of a base such as pyridine, triethylamine-N,N-dimethylamino pyridine or mixtures thereof. The amount of basemay range from 1 to 5 equivalents, based on the amount of the compoundof formula (XXIII). The reaction may be carried out in solvents likedichloromethane, chloroform, dichloroethane, 1,4-dioxane, xylene and thelike. The reaction may be carried out at a temperature in the range of0° C. to 120° C., preferably at a temperature in the range of 15° C. to50° C. The duration of the reaction may range from 0.25 to 12 hpreferably from 0.5 to 5 h.

d) Reaction of compound of formula (XXIV) with a compound of formula(XXV) ##STR45## to yield a compound of formula (XX) defined above. Thereaction proceeds through the intermediate formation of compound offormula (XXVI). ##STR46##

The reaction of compound of formula (XXIV) with a compound of formula(XXV) to produce a compound of general formula (XX) may be carried outin neat or in the presence of solvents such as xylene, toluene, THF,dioxane, acetic acid, DMF, DMSO and the like or mixtures thereof. Thereaction may be carried out in au inert atmosphere which may bemaintained by using inert gases such as N₂, Ar or He. The reaction maybe carried out at a temperature in the range of 50° C. to 200° C.,preferably at a temperature in the range of 80° C. to 180° C. Thereaction may be effected in the presence of an acid. The nature of theacid is not critical. Examples of acids include organic acids such asAcOH, C₂ H₅ COOH, p-toluenesulfonic acid and the like, mineral acidssuch as HCl, HBr etc. The duration of the reaction may range from 0.25to 48 hours, preferably from 0.50 to 18 hours, based on solvent,temperature and acid used.

Alternatively, the novel intermediate of formula (XXVI)) may be isolatedand then cyclised to yield a compound of formula (XX).

The reaction of compound of the formula (XXIV) with a compound offormula (XXV) to yield a compound of the formula (XXVI) may be carriedout neat or in presence of solvent such as xylene, toluene, dioxane,DMF, DMSO halogenated hydrocarbons such as CH₂ Cl₂, CHCl₃, ClCH₂ CH₂ Cland the like or mixtures thereof. The reaction may be effected in thepresence of an acid. The nature of the acid is not critical. Examples ofacids used for this reaction includes CH₃ COOH, C₂ H₅ COOH, butyricacid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Thereaction may be carried out in an inert atmosphere which may bemaintained by using inert gases such as N₂, Ar or He. The reaction maybe carried out at a temperature in the range of 25° C. to 180° C.,preferably in the range of 25° C. to 60° C. The reaction is generallyinstantaneous and the duration of the reaction may range from 0.25 to 12h, preferably 0.25 to 2 h.

The cyclisation of the compound of formula (XXVI) to yield a compound ofthe formula (XX) may be carried out neat or in the presence of solventssuch as THF, toluene, xylene, 1,4-dioxane and the like or mixturesthereof The reaction temperature may range from 60° C. to 150° C.depending upon the solvent employed and in the range from 100° C. to200° C. when the reaction is carried out neat. The reaction may beeffected in the presence of acids. The acids normally used includeacetic acid, propionic acid, and pTsOH. The amount of acid used mayrange from 0.1 to 100 equivalents, preferably 0.1 to 10 equivalents. Thereaction can also be carried out in neat acid. The reaction ispreferably carried out in solvents such as THF, toluene, xylene,1,4-dioxane or mixtures thereof in the presence of an acid such asacetic acid, propionic acid, p-TsOH and the like. The duration of thereaction may range from 3 to 48 h preferably from 4 to 18 h, based onsolvent, temperature and acid used.

The term neat as used herein means the reaction is carried out withoutthe use of solvent.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula (I) with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium t-butoxide,calcium hydroxide, magnesium hydroxide and the like, in solvents likeether, THF, methanol, t-butanol dioxane, isopropanol, ethanol etc.Mixture of solvents may be used. Organic bases like lysine, arginine,diethanolamine, choline, guanidine and their derivatives etc. may alsobe used. Alternatively, acid addition salts are prepared by treatmentwith acids such as hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid. phosphoric acid, p-toluenesulphonic acid, methanesulfonicacid, acetic acid, citric acid, maleic acid salicylic acid,hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid,benzoic acid, benzenesulfonic acid, tartaric acid and the like insolvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc.Mixture of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid and the like or chiralbases such as rucine, cinchona alkaloids and their derivatives and thelike.

Various polymorphs of compound of general formula (I) forming part ofthis invention may be prepared by crystallization of compound of formula(I) under different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe nmr spectroscopy, ir spectroscopy, differential scanningcalorimetry, powder X-ray diffractogram or such other techniques.

The present invention also provides a pharmaceutical composition,containing the compounds of the general formula (I), as defined above,their tautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates in combination with the usual pharmaceutically employedcarriers, diluents and the like, useful for the treatment and/orprophylaxis of diseases in which insulin resistance is the underlyingpathophysiological mechanism such as type II diabetes, impaired glucosetolerance, dyslipidaemia, hypertension, coronary heart disease and othercardiovascular disorders including atherosclerosis, insulin resistanceassociated with obesity and psoriasis, for treating diabeticcomplications and other diseases such as polycystic ovarian syndrome(PCOS), certain renal diseases including diabetic nephropathy,glomerulonephritis, glomerular sclerosis, nephrotic syndrome,hypertensive nephrosclerosis, end-stage renal diseases andmicroalbuminuria as well as certain eating disorders, as aldosereductase inhibitors and for improving cognitive functions in dementia.

The pharmaceutical composition may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like, may contain flavourants, sweeteners etc. in suitable solid orliquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. Such compositions typically containfrom 1 to 20%. preferably 1 to 10% by weight of active compound, theremainder of the composition being pharmaceutically acceptable carriers,diluents or solvents.

A typical tablet production method is exemplified below:

    ______________________________________                                        Tablet Production Example:                                                    ______________________________________                                        a)    1) Active ingredient                                                                            10     g                                                   2) Lactose                       110  g                                       3) Corn starch                    35  g                                       4) Carboxymethyl cellulose      44  g                                         5) Magnesium stearate           1  g                                         200  g for 1000 tablets                                                   ______________________________________                                    

The ingredients 1 to 3 are uniformly blended with water and granulatedafter drying under reduced pressure. The ingredient 4 and 5 are mixedwell with the granules and compressed by tabletting machine to prepare1000 tablets each containing 10 mg of active ingredient.

    ______________________________________                                        b)    1) Active ingredient                                                                            10     g                                                    2) Calcium phosphate            90  g                                         3) Lactose                      50  g                                         4) Corn starch                  45  g                                         5) Polyvinyl pyrrolidone        3.5  g                                        6) Magnesium stearate           1.5  g                                      200  g for 1000 tablets                                                   ______________________________________                                    

The ingredients 1 to 4 are uniformly moistened with an aqueous solutionof ingredient 5 and granulated after drying under reduced pressure.Ingredient 6 is added and granules are compressed by a tablettingmachine to prepare 1000 tablets containing 10 mg of active ingredient 1.

The compound of the formula (I) as defined above are clinicallyadministered to mammals, including man, via either oral or parenteralroutes. Administration by the oral route is preferred being moreconvenient and avoiding the possible pain and irritation of injection.However, in circumstances where the patient cannot swallow themedication, or absorption following oral administration is impaired, asby disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.10 to about 200 mg/kg body weight of the subject per day orpreferably about 0.10 to about 30 mg/kg body weight per day administeredsingly or as a divided dose. However, the optimum dosage for theindividual subject being treated will be determined by the personresponsible for treatment, generally smaller doses being administeredinitially and thereafter increments made to determine the most suitabledosage.

Suitable pharmaceutically acceptable carriers include solid fillers ordiluents and sterile aqueous or organic solutions. The active compoundwill be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the compounds can be combined witha suitable solid or liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions and the like. The pharmaceuticalcompositions, may, if desired, contain additional components such asflavourants, sweeteners, excipients and the like. For parenteraladministration, the compounds can be combined with sterile aqueous ororganic media to form injectable solutions or suspensions. For example,solutions in sesame or peanut oil, aqueous propylene glycol and the likecan be used, as well as aqueous solutions of water-solublepharmaceutically-acceptable acid addition salts or salts with base ofthe compounds. The injectable solutions prepared in this manner can thenbe administered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

Preparation 14-[2-[4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde##STR47##

To a stirred suspension of NaH (570 mg, 22.57 mmol 95%) in dry DMF (35ml) at 25° C. was added a solution of4-methyl-2-propyl-1,6-dihydro-6-pyrimidone (2.64 g, 17.36 mmol) in dryDMF. After the effervescence has ceased, anhydrous LiBr (3.51 g, 40.0mmol) was added followed by 4-[2-bromoethoxy]benzaldehyde (4.37 g, 19.08mmol) in dry DMF at the same temperature. The reaction mixture wasimmersed in a preheated oil bath at 70° C. and stirred for 2 h. Thereaction mixture was cooled to room temperature, poured into water andextracted with EtOAc. The combined EtOAc layers were washed with brine,dried over anhydrous Na₂ SO₄ and concentrated. The crude compound waschromatographed over silica gel using 3 7 EtOAc--pet. ether as eluent toobtain the title compound (1.61 g, 31%).

¹ H NMR(CDCl₃): δ9.80 (s, 1H), 7.82 (d, J=8.72 Hz, 2H), 6.95 (d, J 8.72Hz, 2H), 6.20 (s, 1H) 4.45 (t, J=5.30 Hz, 2H), 4.35 (t, J=5.30 Hz, 2H),2.92 (t, J=7.50 Hz, 2H), 2.25 (s, 3H), 1.92-1.70 (m, 2H), 1.20 (t,J=7.50 Hz, 3H).

Preparation 24-[2-[2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde##STR48##

The title compound (0.8 g, 30%) was prepared from2,4-dimethyl-1,6-dihydro-6-pyrimidone (1.3 g, 10.48 mmol) and4-[2-bromoethoxy]benzaldehyde (2,4 g, 10.48 mmol) in the presence of abase K₂ CO₃ (2.89 g, 20.96 mmol) by a similar procedure as described inpreparation 1.

¹ H NMR (CDCl₃) δ9.90 (s, 1H), 7.80 (d, J=8.70 Hz, 2H), 7.02 (d, J=8.70Hz, 2H), 6.20 (s, 1H), 4.50-4.30 (m, 4H), 2.70 (s, 3H), 2.20 (s, 3H).

Preparation 34-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde##STR49##

The title compound (1.7 g, 42%) was prepared from2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.0 g, 14.49 mmol)4-[2-bromoethoxy]benzaldehyde (3.32 g, 14.49 mmol), LiBr (2.9 g, 33.33mmol) and NaH (0.45 g, 18.84 mmol) as base, by a similar procedure tothat described in preparation 1.

¹ H NMR (CDCl₃): δ9.90 (s, 1H), 7.80 (d, J=8.70 Hz, 2H), 6.98 (d, J=8.70Hz, 2H), 6.20 (s, 1H), 4.52-4.25 (m, 4H), 3.02 (q, J=7.40 Hz, 2H), 2.30(s, 3H), 1.40 (t, J=7.40 Hz, 3H),

Preparation 44-[2-[2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde##STR50##

The title compound (1.1 g, 25%) was prepared from2-butyl-4-methyl-1,6-dihydro-6-pyrimidone (2.3 g, 13.85 mmol),4-[2-bromoethoxy]benzaldehyde (3.17 g, 13.85 mmol) in the presence of K₂CO₃ (3.82 g, 27.7 mmol) as base by a similar procedure to that describedin preparation 1.

¹ H NMR (CDCl₃): δ9.90 (s, 1H), 7.84 (d, J=8.72 Hz, 2H), 6.98 (d, J=8.72Hz, 2H), 6.20 (s, 1H), 4.52-4.30 (m, 4H), 2.96 (t, J=7.47 Hz, 2H), 2.26(s, 3H), 1.90-1.70 (m, 2H), 1.70-1.50 (m, 2H), 1.01 (t, J=7.47 Hz, 3H).

Preparation 54-[2-[2-Benzyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde##STR51##

The title compound (2.0 g, 20.6%) was prepared from2-benzyl-4-methyl-1,6-dihydro-6-pyrimidone (5.6 g, 28.0 mmol),4-[2-bromoethoxy]benzaldehyde (17.05 g, 30.1 mmol) in the presence of95% NaH (873 mg, 35.0 mmol) as base by a similar procedure to thatdescribed in preparation 1.

¹ H NMR (CDCl₃): δ9.89 (s, 1H), 7.83 (d, J=8.72 Hz, 2H), 7.45-7.15 (m,5H), 6.98 (d, J=8.72 H, 2H), 6.44 (s, 1H), 4.70 (t, J=4.71 Hz, 2H), 4.30(t, J=4.71 Hz, 2H), 4.14 (s, 2H), 2.42 (s, 3H).

Preparation 64-[2-[2,5-Diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde##STR52##

The title compound (1.42 g, 28%) was prepared from2,5-diethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.70 g, 16.26 mmol) and4-[2-bromoethoxy]benzaldehyde (4.09 g, 17.86 mmol) in the presence of95% NaH (508 mg, 20 mmol) as base by a similar procedure to thatdescribed in preparation 1.

¹ H NMR (CDCl₃): δ9.88 (s, 1H), 7.82 (d, J=8.62 Hz, 2H), 6.97 (d, J=8.62Hz, 2H), 4.50-4.20 (m, 4H), 2.95 (q, J=7.47 Hz, 2H), 2.52 (q, J=7.47 Hz,2H), 2.28 (s, 3H), 1.34 (t, J=7.47 Hz, 3H), 1.09 (t, J=7.47 Hz, 3H).

Preparation 74-[2-[2-Ethyl-4phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde##STR53##

The title compound (2.0 g, 44%) was prepared from2-ethyl-4-phenyl-1,6-dihydro-6-pyrimidone (2.6 g, 13.0 mmol),4-[2-bromoethoxy]benzaldehyde (2.97 g, 13.0 mmol) and LiBr (2.59 g, 29.9mmol) in the presence of NaH as base (0.4 g, 16.9 mmol) by a similarprocedure to that described in preparation 1.

¹ H NMR (CDCl₃) δ9.89 (s, 1H), 8.10-7.95 (m, 2H), 7.83 (d, J=8.72 Hz,2H), 7.55-7.45 (m, 3H), 6.98 (d, J=8.72 Hz, 2H), 6.78 (s, 1H), 4.60-4.40(m, 4H), 3.08 (q, J=7.30 Hz, 2H), 1.48 (t, J=7.30 Hz, 3H).

Preparation 84-[2-[4-N-Acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde##STR54##

The title compound (1.8 g, 66%) was prepared from4-acetylamino-1,2-dihydro-2-pyrimidone (1.8 g, 11.9 mmol) and4-[2-bromoethoxy]benzaldehyde (2.72 g, 11.9 mmol) in the presence of K₂CO₃ (3.28 g, 23.8 mmol) as base by a similar procedure to that describedin preparation 1.

¹ H NMR (CDCl₃): δ9.90 (s, 1H), 8.70 (bs, 1H, D₂ O exchangeable), 7.85(d, J=8.70 Hz, 2H), 7.75 (d, J=7.80 Hz, 1H), 7.42 (d, J=7.80 Hz, 1H),6.95 (d. J=8.70 Hz, 2H), 4.40-4.20 (m, 4H) 2.30 (s, 3H).

Preparation 9 4-[2-[4-Oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde##STR55##

The title compound (1.5 g, 73%) was prepared from4-oxo-3,4-dihydroquinazoline (1.03 g, 7.05 mmol) and4-[2-bromoethoxy]benzaldehyde (1.77 g, 7.7 mmol) in the presence of K₂CO₃ (2.0 g, 14.5 mmol) as base, by a similar procedure to that describedin preparation 1.

¹ H NMR (CDCl₃) δ9.88 (s, 1H), 8.32 (d, J=7.88 Hz, 1H), 8.21 (s, 1H),7.88-7.70 (m, 2H), 7.82 (d, J=8.72 Hz, 2H), 7.60-7.42 (m, 1H), 7.00 (d,J=8.72 Hz, 2H), 4.55-4.25 (m, 4H).

Preparation 104-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde##STR56##

The title compound (0.6 g, 39%) was prepared from2-methyl-4-oxo-3,4-dihydroquinazoline (0.8 g, 5 mmol) and4-[2-bromoethoxy]benzaldehyde (1.37 g, 6 mmol) in the presence of K₂ CO₃(1.38 g, 10.0 mmol) as base, by a similar procedure to that described inpreparation 1.

¹ H NMR (CDCl₃): δ9.85 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.84-7.72 (m,3H), 7.59-7.41 (m, 2H), 7.10 (d, J=7.0 Hz, 2H), 4.50-4.40 (m, 2H),4.40-4.30 (m, 2H), 2.76 (s, 3H).

Preparation 114-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde##STR57##

The title compound (5.0 g, 27%) was prepared from2-ethyl-4-oxo-3,4-dihydroquinazoline (9.2 g, 57.5 mmol) and4-(2-bromoethoxy)benzaldehyde (14.5 g, 69.0 mmol) in the presence of K₂CO₃ (14.6 g, 115.0 mmol) as base, by a similar procedure to thatdescribed in preparation 1.

¹ H NMR (CDCl₃): δ9.86 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.87-7.76 (m,3H), 7.65-4.45 (m, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.60-4.50 (m, 2H).4.50-4.40 (m, 2H), 3.07 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).

Preparation 124-[2-[8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde##STR58##

The title compound (0.26 g, 41%) was prepared from8-aza-2-methyl-4-oxo-3 4-dihydro quinazoline (0.33 g, 2.0 mmol)4-[2-bromoethoxy]benzaldehyde (0.52 g, 2.25 mmol) in the presence of K₂CO₃ (0.57 g, 4.1 mmol) as base by a similar procedure to that describedin preparation 1.

¹ H NMR (CDCl₃): δ9.87 (s, 1H), 9.02-8.90 (m. 1H), 8.58 (d, J=7.30 Hz,1H), 7.82 (d, J=8.72 Hz. 2H), 7.48-7.35 (m, 1H), 6.97 (d, J=8.72 Hz 2H),4.58 (t, J=4.72 Hz, 2H) 4.43 (t, J=4.72 Hz, 2H), 2.91 (s, 3H).

Preparation 134-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde##STR59##

A mixture of 4-hydroxybenzaldehyde (3.21 g, 26.3 mmol) and K₂ CO₃ (3.64g, 26.3 mmol) in dry DMF (50 ml) was stirred for 15 min at 30° C. To theabove stirred mixture a solution of2-chloromethyl-3-methyl-4-oxo-3,4-dihydroquinazoline (5.0 g, 24.0 mmol)was added and stirred further for 90 minutes at the same temperature.The reaction mixture was diluted with EtOAc (200 ml). washed withaqueous Na₂ CO₃ solution (3×50 ml) and then with brine, dried overanhydrous Na₂ SO₄ and concentrated to yield the title compound (5.08 g,72%).

¹ H NMR (CDCl₃): δ9.89 (s, 1H), 8.29 (d, J=7.89 Hz, 1H), 7.85 (d, J=8.71Hz, 2H), 7.80-7.62 (m, 2H), 7.52 (t, J=7.81 Hz, 1H), 7.19 (d, J=8.71 Hz,2H), 5.27 (s, 2H), 3.74 (s, 3H).

Preparation 144-[[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde##STR60##

The title compound (4.24 g, 88%) was prepared from2-chloromethyl-3-ethyl-4-oxo-3,4-dihydro-quinazoline (3,5 g, 15.7 mmol)and 4-hydroxybenzaldehyde (2.10 g, 17.21 mmol) in the presence of K₂ CO₃(2.38 g, 17.26 mmol) as base by a similar procedure to that described inpreparation 13.

¹ H NMR (CDCl₃): δ9.91 (s, 1H), 8.31 (d, J=7.89 Hz. 1H), 7.88 (d, J=8.72Hz, 2H), 7.82-7.68 (m, 2H), 7.65-7.45 (m, 1H), 7.22 (d, J=8.72 Hz, 2H),5.28 (s, 2H), 4.28 (q, J=7.06 Hz, 2H), 1.41 (t, J=7.06 Hz, 3H).

Preparation 154-[[1-methyl-4-oxo-1,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde##STR61##

The title compound (364 mg, 65%) was prepared from2-chloromethyl-1-methyl-4-oxo-1,4-dihydroquinazoline (416 mg, 2.0 mmol)and 4-hydroxybenzaldehyde (244 mg, 2.0 mmol) in the presence of K₂ CO₃(276 mg, 2.0 mmol) as base by a similar procedure to that described inpreparation 13.

¹ H NMR (CDCl₃): δ9.88 (s, 1H), 8.34 (d, J=7.89 Hz, 1H), 7.83 (d, J=8.71Hz, 2H), 7.80 7.70 (m, 1H), 7.60-7.40(m, 2H), 7.22 (d, J=8.71 Hz, 2H),5.34 (s, 2H), 3.91 (s, 3H).

Preparation 163-Methoxy-4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldehyd##STR62##

The title compound (250 mg, 77%) was obtained from2-chloromethyl-3-methyl-4-oxo-3,4-dihydroquinazoline (209 mg, 1.0 mmol)and vanillin (167 mg, 1.1 mmol) in the presence of K₂ CO₃ (276 mg, 2.0mmol) as base by a similar procedure to that described in preparation13.

¹ H NMR (CDCl₃): δ9.88 (s, 1H), 8.29 (d, J=8.30 Hz, 1H), 7.80-7.62 (m,2H), 7.58-7.39 (m, 2H), 7.26 (d, J=8.30 Hz, 2H), 5.30 (s, 2H), 3.90 (s,3H), 3.78 (s, 3H).

Preparation 174-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehydeOxime ##STR63##

To a stirred solution of hydroxylamine hydrochloride (10.0 g, 143.0mmol) and sodium acetate trihydrate (20.0 g, 146.9 mmol) in water (100ml) at 30° C. was added a hot solution of4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(5.72 g, 20.0 mmol) (obtained from preparation 3) in ethanol (100 ml).The reaction mixture was immersed in a preheated oil bath (95° C.) andrefluxed for 3 h. The reaction mixture was then cooled to roomtemperature and concentrated to a volume where crystals of oxime startedseparating out and the mixture was kept aside for 30 min. to 1 h at 25°C. The resultant crystals were filtered and washed with water and driedto obtain the title compound (5.42 g, 90%).

¹ H NMR (CDCl₃ +DMSO-d₆): δ10.56 (s, 1H, OH, D₂ O exchangeable), 8.08(s, 1H), 7.55 (d, J=8.56 Hz, 2H) 6.88 (d, J=8.56 Hz, 2H), 6.20 (s, 1H),4.51-4.40 (m, 2H), 4.40-4.28 (m, 2H), 3.05 (q, J=7.06 Hz, 2H), 2.30 (s,3H), 1.40 (t, J=7.06 Hz, 3H).

Preparation 184-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzylhydroxylamine##STR64##

To a stirred solution of4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehydeoxime (301 mg, 1.0 mmol) (obtained from preparation 17) in a mixture ofmethanol (7 ml) and THF (3 ml) was added 4 N HCl (2 ml) in dioxane at30° C. and stirred for 10 min. at the same temperature. The reactionmixture was basified to pH 9 with 1 N NaOH and extracted with EtOAc(3×10 ml). The combined organic layers were washed with brine and driedover anhydrous Na₂ SO₄ and concentrated to yield the of title compound(272 mg, 90%).

¹ H NMR (CDCl₃): δ7.23 (d, J=8.72 Hz, 2H), 6.80 (d, J=8.72 Hz, 2H), 6.18(s, 1H), 4.45-4.35 (m, 2H), 4.35-4.20 (m, 2H), 3.98 (s, 2H), 3.01 (q,J=7.56 Hz, 2H), 2.22 (s, 3H), 1.32 (t, J=7.56 Hz, 3H).

Preparation 19N-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl]N-hydroxyurea##STR65##

To a stirred solution of4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzylhydroxylamine (303 mg, 1.0 mmol) (obtained from preparation 18) in amixture of water (2 ml) and acetic acid (0.5 ml) was added a solution ofKOCN (343 mg, 3.0 mmol) in water (I ml) and stirred for 1 h at 30° C.The reaction mixture was diluted with water and extracted with ethylacetate (3×10 ml). The combined organic layers were washed with brine,dried over anhydrous Na₂ SO₄ and concentrated to yield the compound (295mg, 85%).

¹ H NMR (CDCl₃): δ7.18 (d, J=8.65 Hz, 2H), 6.90 (d, J=8.65 Hz, 2H), 6.60(bs, 1H, D₂ O exchangeable), 6.15 (s, 1H), 5.85 (bs, 1H, D₂ Oexchangeable), 4.70 (s, 2H), 4.50 (bs, 1H, D₂ O exchangeable), 4.40-4.30(m, 2H), 4.22-4.10 (m, 2H), 2.92 (q, J=7.56 Hz, 2H), 2.20 (s, 3H), 1.20(t, J=7.56 Hz, 3H).

Preparation 204-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]nitrobenzene##STR66##

The title compound (5.2 g, 25%) was prepared from2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (7.65 g, 55.43 mmol),4-[2-bromoethoxy]nitrobenzene (15.0 g, 60.97 mmol), LiBr (11.09 g,127.49 mmol) and 60% NaH (2.76 g, 72.06 mmol) as base by a similarprocedure to that described in preparation 1.

¹ H NMR (CDCl₃): δ8.20 (d, J=8.81 Hz, 2H), 6.94 (d, J=8.81 Hz, 2H), 6.22(s, 1H), 4.55-4.42 (m, 2H), 4.42-4.34 (m, 2H), 2.99 (q, J=7.4 Hz, 2H),2.27 (s, 3H), 1.38 (t, J=7.4 Hz, 3H).

Preparation 214-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]nitrobenzene##STR67##

The title compound (1.246 g, 64%) was prepared from2-ethyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 5.7 mmol) and4-[2-bromoethoxy]nitrobenzene (1.696 g, 6.8 mmol) and K₂ CO₃ (1.58 g,11.49 mmol) as a base by a similar procedure to that described inpreparation 1.

¹ H NMR (CDCl₃): δ8.24 (d, J=7.93 Hz, 1H), 8.18 (d, J=9.20 Hz, 2H),7.82-7.61 (m, 2H), 7.46 (t, J=7.93 Hz, 1H), 6.94 (d, J=9.20 Hz, 2H),4.58 (t, J=4.82 Hz, 2H), 4.44 (t, J=4.82 Hz, 2H), 3.09 (q, J=7.38 Hz,2H), 1.46 (t, J=7.38 Hz, 3H).

Preparation 224-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]aniline##STR68##

A solution of4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]nitrobenzene(1.0 g. 3.3 mmol) (obtained from preparation 20) in 1.4-dioxane (20 ml)was reduced with hydrogen in the presence of 10% palladium on charcoal(100 mg) at 30 psi for 16 h. The mixture was filtered through a bed ofcelite and washed with dioxane and evaporated to dryness under reducedpressure to yield the title compound (625 mg, 70%).

¹ H NMR (CDCl₃) δ6.78-6.52 (m, 4H), 6.18 (s, 1H), 4.38 (t, J=4.98 Hz,2H), 4.19 (t, J=4.98 Hz, 2H), 2.99 (q, J=7.47 Hz, 2H), 2.24 (s, 3H),1.33 (t, J=7.47 Hz, 3H).

Preparation 234-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]aniline ##STR69##

The title compound (1.107 g, 98%) was prepared from4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]nitrobenzene(1.246 g, 3.67 mmol) (obtained from preparation 21) by a similarprocedure to that described in preparaton 22.

¹ H NMR (CDCl₃): δ8.24 (d, J=7.93 Hz, 1H), 7.80-7.60 (m, 2H), 7.43 (t,J=7.93 Hz, 1H), 6.80-6.50 (m, 4H), 4.51 (t, J=5.19 Hz, 2H), 4.24 (t,J=5.19 Hz, 2H), 3.10 (q, J=7.34 Hz, 2H), 1.42 (t, J=7.34 Hz, 3H).

Preparation 24 Ethyl2-Bromo-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]propanoate##STR70##

To a stirred solution of4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]aniline(2.80 g, 10.26 mmol) (obtained from preparation 22) in acetone (10 ml)was added aqueous HBr (47%, 1 ml) and stirred for 10 min. at 0° C. Tothe above reaction mixture a solution of NaNO₂ (850 mg, 12.30 mmol) inwater (1.7 ml) was added slowly dropwise at 0° C. and stirring wascontinued further for 30 min at the same temperature. To this reactionmixture, ethyl acrylate (6.77 ml, 62.0 mmol) was added and allowed towarm to 30° C. Catalytic amount of copper (1) iodide (20 mg) was addedin one portion and the reaction mixture was stirred flier for 1 h at 30°C. Acetone was removed under reduced pressure and the resultant residuewas extracted with EtOAc (3×10 ml). The combined EtOAc layers werewashed with dilute NH3 solution, water, followed by brine; dried overanhydrous Na₂ SO₄ and concentrated to afford the crude compound whichwas purified by flash chromatography using 40% EtOAc/petroleum ether aseluent to yield the title compound (2.47 g, 55%).

¹ H NMR (CDCl₃): δ7.11 (d, J=8.63 H, 2H), 6.78 (d, J=8.63 Hz, 2H), 6.19(s, 1H), 4.50-4.32 (m, 2H), 4.30-4.02 (m, 5H), 3.38 (dd, J=13.72, 8.31Hz, 1H), 3.17 (dd, J=13.72, 7.06 Hz, 1H), 3.10-2.90 (m, 2H), 2.25 (s,3H), 1.35 (t, J=7.47 Hz, 3H), 1.24 (t, J=7.05 Hz, 3H).

Preparation 25 Ethyl2-Bromo-3-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl]propanoate##STR71##

The title compound (671 mg, 55%) was prepared from4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]aniline (800 mg,2.58 mmol) (obtained from preparation 23), NaNO₂ (214 mg, 3.1 mmol) andethyl acrylate (1.7 ml, 1.574 g, 15.74 mmol) by a similar procedure tothat described in preparation 24.

¹ H NMR (CDCl₃): δ8.23 (d, J=7.88 Hz, 1H), 7.80-7.55 (m, 2H), 7.52-7.30(m, 1H), 7.15-7.01 (m, 2H), 6.77 (d, J=8.71 Hz, 2H), 4.52 (t, J=5.03 Hz,2H), 4.45-4.30 (m, 1H), 4.30 (t, J=5.03 Hz, 2H), 4.20-4.00 (m, 2H), 3.35(dd, J=14.12, 8.71 Hz, 1H), 3.20-3.00 (m, 3H), 1.43 (t, J=7.34 Hz, 3H),1.20 (t, J=7.34 Hz, 3H).

Preparation 265-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]-2-iminothiazolidine-4-one Hydrochloride ##STR72##

A mixture of ethyl2-bromo-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]propaneate(1.70 g, 3.89 mmol) (obtained from preparation 24), fused sodium acetate(637 mg, 7.78 mmol) and thiourea (592 mg, 7.78 mmol) in ethanol (10 ml)was refluxed for 12 h. The reaction mixture was cooled to roomtemperature and the resultant solid was filtered and dried to afford thetitle compound (1.35 g, 89%).

¹ H NMR (CDCl₃): δ7.12 (d, J=8.59 Hz, 2H), 6.76 (d, J=8.59Hz, 2H),6.12(s, 1H), 4.50-4.30 (m, 3H), 4.30-4.15 (m, 2H), 3.40 (dd, J=14.11,3.74 Hz, 1H), 2.98 (q, J=7.47 Hz, 2H). 2.85 (dd, J=14.11, 9.43 Hz, 1H),2.23 (s, 3H), 1.32 (t, J=7.47 Hz, 3H).

Preparation 275-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethyl]-2-imino thiazolidine-4-one Hydrochloride ##STR73##

The title compound (329 mg, 78%) was prepared from ethyl2-bromo-3-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl]propanoate(473 mg, 1.0 mmol) (obtained from preparation 25), sodium acetate (164mg, 2.0 mmol) and thiourea (152 mg, 2.0 mmol) by a similar procedure tothat described in preparation 26.

¹ H NMR (CDCl₃): δ8.12 (d, J=7.88 Hz, 1H), 7.80 (t, J=7.03 Hz, 1H), 7.62(d, J=7.88 Hz, 1H), 7.49 (t, J=7.03 Hz, 1H), 7.12 (d, J=7.58 Hz, 2H),6.84 (d, J=7.58 Hz, 2H), 4.50 (dd, J=9.43, 3.72 Hz, 1H), 4.46 (t, J=5.31Hz, 2H), 4.25 (d, J=5.31 Hz, 2H), 3.25 (dd, J=14.11, 3.72 Hz, 1H), 3.04(q, J=7.17 Hz, 2H), 2.81 (dd, J=14.11, 9.43 Hz, 1H), 1.31 (t, J=7.19 Hz,3H).

Preparation 283-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]-2-hydroxypropanoicAcid ##STR74##

A mixture of ethyl2-bromo-[3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl-ethoxy]phenyl]propanoate(438 mg, 1.0 mmol) (obtained from preparation 24), sodium hydroxide (44mg, 1.1 mmol) and calcium carbonate (100 mg, 1.0 mmol) in 1,6-dioxane (2ml) and water (3 ml) was refluxed for 10 h. The reaction mixture wascooled to room temperature and acidified to pH 4 with 2N HCl andextracted with EtOAc (2×10 ml). The combined organic layers were washedwith brine, dried over Na₂ SO₄ and concentrated to afford the titlecompound (92 mg, 27%).

¹ H NMR (CDCl₃ +DMSO-d₆): δ7.12 (d, J=8.61 Hz, 2H), 6.78 (d, J=8.61 Hz,2H), 6.19 (s, 1H), 4.50-4.32 (m, 2H), 4.30-4.05 (m, 3H), 3.10-2.60 (m,4H), 2.25 (s, 3H), 1.30 (t, J=7.20 Hz, 3H).

Preparation 29 Ethyl3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]-2-hydroxypropanoate##STR75## Method A

A solution of 3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro1-pyrimidinyl]ethoxy]phenyl]-2-hydroxypropanoic acid (346 mg, 1.0 mmol)(obtained from preparation 28) in ethanol (3 ml) containing concentratedhydrochloric acid (0.1 ml) was refluxed for 10 h. The solution wascooled to room temperature, diluted with water and extracted with EtOAc(2×10 ml). The combined organic extracts were washed with brine, driedover anhydrous Na₂ SO₄ and concentrated to yield the title compound (97mg, 26%).

Method B

A mixture of ethyl2-bromo-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]propanoate(1.0 g, 2.28 mmol) (obtained from preparation 24) formamide (225 μl) andwater (45 μl, 45 mg, 2.5 mmol) was heated at 160° C. for 3 h. Water (45μl) was added further and stirred for 2 h at 175° C. The reactionmixture was cooled to room temperature, diluted with EtOAc (10 ml)washed with brine, dried over anhydrous Na₂ SO₄ and concentrated toyield the crude compound which was purified by flash chromatography toafford the title compound (306 mg, 36%).

¹ H NMR (CDCl₃): δ7.11 (d, J=8.62 Hz, 2H), 6.77 (d, J=8.62 Hz, 2H), 6.18(s, 1H), 4.50-4.31 (m, 2H), 4.30-4.05 (m, 5H), 3.10-2.80 (in, 4H), 2.25(s, 3H), 1.40-1.15 (m, 6H).

Preparation 305-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]-2-thio-1,3-oxazolidine-4-one ##STR76##

An inmate mixture of4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(286 mg, 1.0 mmol) (obtained from preparation 3),2-thio-1,3-oxazolidine-4-one (175 mg, 1.5 mmol) and anhydrous sodiumacetate (246 mg, 3.0 mmol) was heated at 120° C. under reduced pressure(2.0 torr.) for 90 min. After cooling, the reaction mixture was pouredinto ethyl acetate (80 ml) and water (20 ml) and stirred for 30 min, theaqueous layer was separated and acidified to pH 4 with 2N HCl. The solidseparated was filtered and dried to yield the title compound (207 mg,54%).

¹ H NMR (CDCl₃): δ7.76 (d, J=8.62 Hz, 2H), 6.93 (d, J=8.62 Hz, 2H), 6.59(s, 1H), 6.17 (s, 1H), 4.50-4.30 (i, 4H), 2.98 (q, J=7.47 Hz, 2H), 2.27(s, 3H), 1.35 (t, J=7.47 Hz, 3H).

Preparation 314-[2-[2,5,6-Trimethyl-4-oxo-3,4-dihydro-thieno-[2,3-d]pyrimidin-3yl]ethoxy]benzaldehyde##STR77##

The title compound (5.04 g, 27%) was prepared from2,5,6-trimethyl-4-oxo-thienopyrimidine (10.59 g, 54.6 mmol),4-[2-bromoethoxy]benzaldehyde (12.82 g, 56 mmol) and K₂ CO₃ (15.04 g,109 mmol) as base by a similar procedure to that described inpreparation 1.

¹ H NMR (CDCl₃): 8 9.88 (s, 1H), 7.82 (d, J=8.72 Hz, 2H), 6.98 (d,J=8.72 Hz, 2H), 4.60-4.30 (m, 4H), 2.78 (s, 3H), 2.46 (s, 3H), 2.37 (s,3H).

Preparation 324-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]nitrobenzene##STR78##

The title compound (1.2 g, 60%) was prepared from2-methyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 6.25 mmol) and4-[2-bromoethoxy]nitrobenzene (1.69 g, 6.9 mmol) and K₂ CO₃ (1.73 g,12.5 mmol) as a base by a similar procedure to that described inpreparation 1.

¹ NMR (CDCl₃): 8.24 (d, J=7.5 Hz, 1H), 8.18 (d, J=9.22 Hz, 2H), 7.75 (t,J=7.50 Hz, 1H), 7.63 (d, J=7.50 Hz, 1H), 7.46 (t, J=7.50, 1H), 6.94 (d,J=9.22 Hz, 2H), 4.58 (t, J=4.98 Hz, 2H), 4.46 (t, J=4.98 Hz, 2H), 2.82(s, 3H).

Preparation 334-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]aniline ##STR79##

The title compound (9.07 mg, 99%) was prepared from4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]nitrobenzene (1.0g, 3.1 mmol) (obtained from preparation 32) by a similar procedure tothat described in preparation 22.

¹ H NMR (CDCl₃) δ: 8.24 (d, =7.50 Hz, 1H), 7.69 (t, J=4.13 Hz, 1H), 7.62(d, J=7.50 Hz, 1H), 7.43 (t, J=7.50 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H),6.60 (d, J=8.80 Hz, 2H), 4.49 (t, J=4.98 Hz, 2H), 4.26 (t, J=4.98 Hz,2H), 2.81 (s, 3H).

Preparation 34 Ethyl2-Bromo-3-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl]propanoate##STR80##

The title compound (3.4 g, 58%) was prepared from4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]aniline (3.75 g,12.7 mmol) (obtained from preparation 33, NaNO₂ (955 mg, 13.8 mmol) andethyl acrylate (8.2 mL, 7.62 g, 76.2 mmol) by a similar procedure tothat described in preparation 24.

¹ H NMR (CDCl₃): δ8.23 (d, J=7.50 Hz, 1H), 7.80-7.60 (m, 2H), 7.43 (t,J=7.50 Hz, 1H), 7.31 (d, J=7.50 Hz, 1H), 7.10 (d, J=7.50 Hz, 1H),6.85-6.70 (m, 2H), 4.53 (t, J=4.98 Hz, 2H), 4.33 (t, J=4.98 Hz, 2H),4.31 (dd, J=8.71, 3.83 Hz, 1H), 4.12 (q, J=5.80 Hz, 2H), 3.35 (dd,J=14.12, 8.71 Hz, 1H), 3.13 (dd, J=14.12, 3.83 Hz, 1H), 2.80 (s, 3H),1.22 (t, J=5.8 Hz, 3H).

Preparation 355-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethyl]-2imino thiazolidine-4-one Hydrochloride ##STR81##

The title compound (1.8 g, 60%) was obtained from ethyl2-bromo-3-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylpropanoate [3,4 g, 7.4 mmol) (obtained from preparation 34), sodiumacetate (2.0 g, 14.8 mmol) and thiourea (1.13 g, 14.8 mmol) by a similarprocedure to that described in preparation 26.

¹ H NMR (CDCl₃) δ: 8.79 (bs, 1H, D₂ O exchangeable), 8.11 (d, J=7.50 Hz,1H), 7.80 (t, J 7.50 Hz, 1H), 7.59 (d, J=7.50 Hz, 1H), 7.48 (t, J=7.50Hz, 1H), 7.12 (d, J=8.48 Hz, 2H), 6.86 (d, J=8.48 Hz, 2H), 4.51 (dd,J=9.54, 3.91 Hz, 1H), 4.44 (t, J=4.98 Hz, 2H), 4.26 (t, J 4.98 Hz, 2H),3.22 (dd, J=14.11, 3.91 Hz, 1H), 2.82 (dd, J=14.11, 9.54 Hz, 1H), 2.71(s, 3H).

Preparation 364-[2-[2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde##STR82##

The title compound (138 mg, 40%) was prepared from2-ethyl-4-trifuoromethyl-(1,6-dihydro-6-pyrimidone (200 mg, 1.04 mmol)and 4-[2-bromoethoxy]benzaldehyde (238.5 mg, 1.04 mmol) in presence ofK₂ C₀ ₃ (287.5 mg, 2.08 mmol) as base by a similar procedure to thatdescribed in preparation 1.

¹ H NMR (CDCl₃): δ9.89 (s, 1H), 7.83 (d, J=8.67 Hz, 2H), 6.95 (d, J=8.67Hz, 2H), 6.70 (s, 1H), 4.50 (t, J=4.66 Hz, 2H), 4.39 (t, J=4.66 Hz, 21),3.1 (q, J=7.4 Hz, 2H), 1.4 (t, J=7.4 Hz, 3H).

Preparation 37 Ethyl[4-[[2,4-dioxo-1,3-thiazolidine-5yl]methyl]phenoxy]acetate ##STR83##Method A

A solution of ethyl[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methylene]phenoxy]acetate (10 g) in1,4-dioxane (200 mL) was reduced with hydrogen in the presence of 5%palladium on charcoal (15 g) at 40 psi pressure for 24 h. The mixturewas filtered through a bed of celite. The filtrate was evaporated todryness under reduced pressure to afford the title compound (9.5 g,95%).

Method B

To magnesium turnings (6.6 g, 0.277 mol) in methanol (150 mL) was addeda solution of ethyl[4-[[2,4--dioxo-1,3-thiazolidine-5-yl]methylene]phenoxy]acetate (5 g,16.3 mmol) in methanol (50 mL) and stirred for 12 h, maintaining thetemperature below 50° C., when the reaction initiates as evidenced byhydrogen evolution and heat generation. The reaction mixture was pouredinto iced water (150 mL), neutralised with 10% aqueous hydrochloricacid, and the solution was extracted with ethyl acetate (3×100 mL). Thecombined organic extracts were washed with water (150 mL) brine (100 mL)and dried (MgSO₄), and the solvent was removed under reduced pressure.The residue was chromatographed on silica gel in 2% methanol indichloromethane to give the title compound (2.3 g, 46%. mp: 107° C.

¹ H NMR (CDCl₃): δ8.5 (bs, 1H, D₂ O exchangeable), 7.20 (d, J=8.50 Hz,2H), 7.06 (d, J=8.50 Hz, 2H), 4.65 (s, 2H), 4.53 (dd, J=9.39, 3.74 Hz,1H), 4.32 (q, J=7.20 Hz, 2H), 3.50 (dd, J=14.12, 3.74 Hz, 1H), 3.14 (dd,J=14.12, 9.39 Hz, 1H), 1.34 (t, J=7.17 Hz, 3H).

Preparation 38 [4-[[2,4-Dioxo-1,3-thiazolidine-5yl]methyl]phenoxy]aceticAcid ##STR84##

To a stirred solution of ethyl[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetate (110 g, 0.36mol) in methanol (0.65 L) was added as solution of Na₂ CO₃ (200 g, 1.88mol) in water (0.65 L) and stirred for 5 h at 25 to 30° C. Aftercompletion of the reaction, methanol was removed under reduced pressure;water was added to the residue and was acidified with hydrochlori acid.The precipitated white solid was filtered and dired to yield the titlecompound (80 g, 80%). mp: 181-183° C.

1H NMR (DMSO-d₆): δ12.40 (bs, 1H, D₂ O exchangeable), 8.60 (bs, 1H, D₂ Oexchangeable)., 7.16 (d, J=8.40 Hz, 2H), 6.50 (d, J=8.40 Hz, 2H), 4.87(dd, J=9.14, 4.20 Hz, 1H), 4.65 (s, 2H), 3.32 (dd, J=14.12, 4.20 Hz,1H), 3.05 (dd, J=14.12, 9.14 Hz, 1H).

Preparation 39 5-[[4-[N-[MethylBenzamide-2-yl]aminocarbonyl]methoxy]phenylMethyl]thiazolidine-2,4-dione ##STR85## Method A

To a stirred solution of14-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (1.9 g,6.75 mmol) in dichloromethane (15 mL) was added triethyl amine (1.876mL, 1.36 g, 13.48 mmol) followed by pivaloyl chloride (0.913 mL, 899 mg,5.46 mmol) at 0° C. and was furthe stirred for 1 h at 0° C. The reactionmixture was added to a solution of 2-amino-N-methyl benzamide (920 mg,6.13 mmol) in acetic acid (10 mL) and xylene (10 mL) and the reactionmixture was stirred for 30 min at 250C. The solvents were removed underreduced pressure and the product was purified to yield the titlecompound (2.51 g, 91%). mp =201-203° C.

Method B

To a stirred solution of[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (1.9 g,6.75 mmol) in xylene (15 mL) was added thionyl chloride (2.46 mL, 4.02g, 33.75 mmol) and refluxed for 1 h. The reaction mixture was cooled toroom temperature and excess thionyl chloride was removed under reducedpressure. The residue was added to a solution of 2-amino-N-methylbenzamide (920 mg, 6.13 mmol) in acetic acid (10 mL) and xylene (10 mL)and stirred for 1 h at 25° C. The solvents were removed under reducedpressure and the product was purified to yield the title compound (2.4g, 86%).

¹ H NMR (CDCl₃, 200 MHz) δ: 12.21 (s, 1H, D₂ O exchangeable), 11.7 (bs,1H, D₂ O exchangeable), 8.63 (d, J=8.30 Hz, 1H), 7.96 (bs, 1H, D₂ Oexchangeable), 7.65 (d, J=7.80 Hz, 1H), 7.47 (t, J=7.80 Hz, 1H),7.30-6.96 (m, 5H), 4.60 (s, 2H), 4.48 (dd, J=9.6, 3.70 Hz, 1H), 3.45(dd, J=13.70, 3.70 Hz, 1H), 3.05 (dd, J=13.70, 9.60 Hz, 1H), 2.94 (d,J=3.74 Hz, 3H).

EXAMPLE 15-[4-[2-[1Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione ##STR86##

A mixture of4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(10 g, 24.5 mmol) (obtained from preparation 1), thiazolidine-2,4-dione(3,5 g, 30 mmol), benzoic acid (388 mg, 3.18 mmol) and piperidine (352μl, 303 mg, 3.68 mmol) in toluene (50 ml) was refluxed for 1 h withcontinuous removal of water. The reaction mixture was cooled to roomtemperature and the resultant crystalline compound was filtered andwashed with water and dried to afford the title compound (12.3 g, 99%),mp 240-242° C.

¹ H NMR (DMSO-d₆): δ12.40 (bs, 1H, D₂ O exchangeable), 7.75 (s, 1H),7.54 (d, J=8.72 Hz, 2H), 7.02 (d, J=8.72 Hz, 2H), 6.15 (s, 1H),4.45-4.15 (m, 4H), 2.91 (t, J=7.65 Hz, 2H), 2.20 (s, 3H), 1.90-1.65 (m,2H), 1.06 (t, J 7.65 Hz, 3H).

EXAMPLE 25-[4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione ##STR87##

The title compound (0.98 g, 95%) was obtained from4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(0.8 g, 2.8 mmol) (obtained from preparation 2) andthiazolidine-2,4-dione (0.344 g, 2.8 mmol) by a similar procedure tothat described in example 1, mp 235° C.

¹ H NMR (CDCl₃): δ8.50 (bs, 1H, D₂ O exchangeable), 7.80 (s, 1H), 7.48(d, J=8.40 Hz, 2H), 6.98 (d, J=8.40 Hz, 2H), 6.21 (s, 1H), 4.52-4.30 (m,4H), 2.70 (s, 3H), 2.25 (s, 3H).

EXAMPLE 35-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione ##STR88##

The title compound (2.13 g, 92%) was obtained from4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(1.7 g, 5.94 mmol) (obtained from preparation 3) andthiazolidine-2,4-dione (0.695 g, 5.94 mmol) by a similar procedure tothat described in example 1, mp248-250° C.

¹ H NMR (CDCl₃ +DMSO-d₆): δ12.25 (bs, 1H, D₂ O exchangeable), 7.78 (s,1H), 7.40 (d, J=7.40 Hz, 2), 7.0 (d, J=7.40 Hz, 2H), 6.20 (s, 1H),4.48-4.24 (m, 4H), 3.0 (q, J=6.4 Hz, 2H), 2.20 (s, 3H), 1.28 (t, J=6.4Hz, 3H).

EXAMPLE 45-[4-[2-[2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione ##STR89##

The title compound (1.2 g, 83%) was obtained from4-[2-[2-butyl-4-methyl-6-oxo-1,6dihydro-1-pyrimidinyl]ethoxy]benzaldehyde (1.1 g, 3,5 mmol) (obtainedfrom preparation 4) and thiazolidine-2,4-dione (410 mg, 3,5 mmol) by asimilar procedure to that described in example 1, mp 209° C.

¹ H NMR (CDCl₃): δ7.80 (s, 1H), 7.40 (d, J=8.63 Hz, 2H), 6.95 (d, J=8.63Hz, 2H), 6.21 (s, 1H), 4.55-4.22 (m, 4H), 2.95 (t, J=7.47 Hz, 2H), 2.25(s, 3H), 1.85-1.60 (m, 2H), 1.60-1.40) (m, 2H), 0.99 (t, J=7.10 Hz, 3H).

EXAMPLE 55-[4-[2-[2-Benzyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione ##STR90##

The title compound (1.70 g, 66%) was obtained from4-[2-[2-benzyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(2.0 g, 5.74 mmol) (obtained from preparation 5) andthiazolidine-2,4-dione (0.74 g, 6.4 mmol) by a similar procedure to thatdescribed in example 1, mp 223° C.

¹ H NMR (CDCl₃ +DMSO-d₆): δ7.74 (s, 1H), 7.44 (d, J=8.71 Hz, 2H),7.40-7.10 (m, 5H), 6.95 (d, J=8.71 Hz, 2H), 6.26 (s, 1H), 4.38 (s, 2H),4.35-4.10 (m, 4H), 2.32 (s, 3H).

EXAMPLE 65-[4-[2-2,5-Diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]thiazolidine2,4-dione ##STR91##

The title compound (881 mg, 92%) was obtained from4-[2-[2,5-diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(730 mg, 2.32 mmol) (obtained from preparation 6) andthiazolidine-2,4-dione (451 mg, 2.55 mmol) by a similar procedure tothat described in example 1, mp 252-254° C.

¹ H NMR (CDCl₃ +DMSO-d₆): δ12.08 (bs, 1H, D₂ O exchangeable), 7.69 (s,1H), 7.44 (d, J=8.58 Hz, 2H), 6.97 (d, J=8.58 Hz, 2H), 4.50-4.20 (m,4H), 2.93 (q, J=7.43 Hz, 2H), 2.50 (q, J=7.43 Hz, 2H), 2.26 (s, 3H),1.33 (t, J=7.43 Hz, 3H), 1.07 (t, J=7.43 Hz, 3H).

EXAMPLE 75-[4-[2-[2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione ##STR92##

The title compound (2.2 g, 88%) was obtained from4-[2-[2-ethyl-4phenyl-6-oxo-1-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(2.09 g, 6.0 mmol) (obtained from preparation 7) andthiazolidine-2,4-dione (0.702 g, 6.0 mmol) by a similar procedure tothat described in example 1, mp 234° C.

¹ H NMR (DMSO-d₆): 12.58 (bs, 1H, D₂ O exchangeable), 8.22-8.05 (m, 2H),7.74 (s, 1H), 7.66-7.38 (m, 5H), 7.11 (d, J=8.30 Hz, 2H), 6..92 (s, 1H),4.48-4.20 (m, 4H), 3.06 (q, J=7.06 Hz, 2H), 1.35 (t, J=7.06 Hz, 3H).

EXAMPLE 8 5-[4-[2-[4-Oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione ##STR93##

The title compound (1.91 g, 84%) was obtained from4-[2-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde (1.7 g, 5.78mmol) (obtained from preparation 9) and thiazolidine-2,4-dione (678 mg,5.79 mmol) by a similar procedure to that described in example 1, mp242-244° C.

¹ H NMR (CDCl₃ +DMSO-d₆): δ12.56 (bs, 1H, D₂ O exchangeable), 8.42 (s,1H), 8.18 (d, J=7.89 Hz, 1H), 7.84 (t, J=7.47 Hz, 1H), 7.72 (s, 1H),7.72-7.50 (m, 2H), 7.54 (d, J=8.72 Hz, 2H), 7.11 (d, J=8.72 Hz, 2H),4.40 (s, 4H).

EXAMPLE 95-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione ##STR94##

The title compound (4.28, 93%) was obtained from4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde (3,4g, 11.04 mmol) (obtained from preparation 10) and thiazolidine-2,4-dione(1,6 g, 13.8 mmol) by a similar procedure to that described in example1, mp 278° C.

¹ H NMR (DMSO-d₆): δ12.58 (bs, 1H, D₂ O exchangeable), 8.19 (d, J=8.0Hz, 1H), 7.89-7.44 (m, 6H), 7.03 (d, J=8.7 Hz, 2H), 4.58-4.42 (m, 2H),4.42-4.25 (m, 2H), 2.81 (s, 3H).

EXAMPLE 105-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethylene]thiazolidine 2,4-dione ##STR95##

The title compound (0.42 g, 92%) was obtained from4-[2-[2-ethyl-4-oxo3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde (0.35g, 1.08 mmol) (obtained from preparation 11) and thiazolidine-2,4-dione(0.16 g, 1.4 mmol) by a similar procedure to that described in example1, mp 257° C.

¹ H NMR (DMSO-d₆): δ12.58 (bs, 1H, D₂ O exchangeable), 8.15 (d, J=8.0Hz, 1H), 7.82-7.44 (m, 6H), 7.08 (d, =8.0 Hz, 2H), 4.47-4.40 (,2H),4.40-4.30 (m, 2H), 3.08 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).

EXAMPLE 115-[4-2-[8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethylene]thiazolidine2,4-dione ##STR96##

The title compound (0.25 g, 68%) was obtained from4-[2-[8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde(0.28 g, 0.9 mmol) (obtained from preparation 12) andthiazolidine-2,4-dione (0.106 g, 0.9 mmol) by a similar procedure tothat described in example 1, mp 276° C.

¹ H NMR (CDCl₃ +DMSO-d₆): δ9.00-8.90 (m, 1H), 8.51 (d, J=7.30 Hz, 1H),7.72 (s, 1H), 7.51 (d, J=8.72 Hz, 2H), 7.55-7.45 (m, 1H), 7.05 (d,J=8.72 Hz, 2H), 4.60-4.50 (m, 2H), 4.50-4.38 (m, 2H), 2.85 (s, 3H).

EXAMPLE 125-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylMethylene]thiazolidine-2,4-dione ##STR97##

The title compound (11.10 g, 96%) was obtained from4-[[3-methyl-4-oxo3,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde (9.0g, 30.61 mmol) (obtained from preparation 13) and thiazolidine-2,4-dione(3.6 g, 30.61 mmol) by a similar procedure to that described in example1, mp 280° C.

¹ H NMR (CDCl₃ +DMSO-d₆): δ12.38 (bs, 1H, D₂ O exchangeable), 8.19 (d,J=7.47 Hz, 1H), 7.82-7.60 (m, 2H), 7.72 (s, 1H), 7.53 (d, J=8.7 Hz, 2H),7.60-7.48 (m, 1H), 7.23 (d, J=8.72 Hz, 2H), 5.35 (s, 2H), 3.68 (s, 3H).

EXAMPLE 135-[4-[[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylMethylene]thiazolidine-2,4-dione ##STR98##

The title compound (3.3 g, 83%) was obtained from4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde (3.0g, 9.74 mmol) (obtained from preparation 14) and thiazolidine-2,4-dione(1.14 g, 9.74 mmol) by a similar procedure to that described in example1, mp 260-261° C.

¹ H NMR (CDCl₃ +DMSO-d₆): δ12.58 (bs, 1H, D₂ O exchangeable), 8.18 (d,J=7.88 Hz, 1H), 7.92-7.74 (m, 1H), 7.78 (s, 1H), 7.74-7.54 (m, 2H), 7.61(d, J=8.72 Hz, 2H), 7.29 (d, J=8.72 Hz, 2H), 5.40 (s, 2H), 4.14 (q,J=6.84 Hz, 2H), 1.34 (t, J=6.84 Hz, 3H).

EXAMPLE 145-[4-[[1-Methyl-4-oxo-1,4-dihydro-2-quinazolinyl]methoxy]phenylMethylene]thiazolidine-2,4-dione ##STR99##

The title compound (310 mg, 79%) was obtained from4-[[1-methyl-4-oxo-1,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde (294mg, 1.0 mmol) (obtained from preparation 15) and thiazolidine-2,4-dione(117 mg, 1.0 mmol) by a similar procedure to that described in example1.□

¹ H NMR (DMSO-d₆): δ8.09 (d, J=7.88 Hz, 1H), 8.00-7.04 (m, 4H), 7.58 (d,J 8.72 Hz, 2H), 7.24 (d, J=8.72 Hz, 2H), 5.41 (s, 2H), 3.86 (s, 3H).

EXAMPLE 155-[3-Methoxy-4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylMethylene]thiazolidine-2,4-dione ##STR100##

The title compound (235 mg, 90%) was obtained from3-methoxy-4-[[3-methyl-4-oxo-3,4-dihydroquinazolinyl]methoxy]benzaldehyde(200 mg, 0.62 mmol) (obtained from preparation 16) andthiazolidine-2,4-dione (79 mg, 0.68 mmol) by a similar procedure to thatdescribed in example 1, mp 244-246° C.

¹ H NMR (DMSO-d₆ +CDCl₃) δ12.25 (bs, 1H, D₂ O exchangeable) 8.02 (d,J=7.20 Hz, 1H), 7.82-7.60 (m, 2H), 7.66 (s, 1H), 7.51 (t, J=7.20 Hz,1H), 7.38-7.03 (m, 3H), 5.52 (s, 2H), 3.91 (s, 3H), 3.68 (s, 3H).

EXAMPLE 165-[4-[2-[4-Acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione ##STR101##

The title compound (1.8 g, 81%) was obtained from4-[2-[4-acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(1.7 g, 5.65 mmol) (obtained from preparation 8) andthiazolidine-2,4-dione (0.661 g, 5.65 mmol) by a similar procedure tothat described in example 1, mp 274° C.

¹ H NMR (CDCl₃ +DMSO-d₆): 8 12.56 (bs, 1H, D₂ O exchangeable), 10.85 (s,1H, D₂ O exchangeable), 8.11 (d, J=7.2 Hz, 1H), 7.74 (s, 1H), 7.55 (d,J=S.30 Hz, 2H), 7.17 (d, J=7.20 Hz, 1H), 7.11 (d, J=8.30 Hz, 2H),4.40-4.05 (m, 4H), 2.08 (s, 3H).

EXAMPLE 175-[4-[2-[4-methyl-2-Propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl] thiazolidine-2,4-dione ##STR102##

A solution of 5-[4-[2-[4-methyl-2-propyl-6-oxo1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione(5.0 g, 12.46 mmol) obtained from example 1 in 1,4-dioxane (75 ml) wasreduced with hydrogen in the presence of 10% palladium on charcoal (12.0g) at 60 psi pressure for 40 h. The mixture was filtered through a bedof celite. The filtrate was evaporated to dryness under reducedpressure, purified by column chromatography (2: 1 EtOAc/petroleum etheras eluent) followed by crystallisation (CH₂ C₁₂) to afford the titlecompound (4.6 g, 92%), mp 144-146° C.

¹ H NMR (CDCl₃): δ8.25 (bs, 1H, D₂ O exchangeable) 7.12 (d, J=8.48 Hz,2H), 6.79 (d, J=7.48 Hz, 2H), 6.21 (s, 1H), 4.47 (dd, J=9.36, 4.06 Hz,1H), 4.41 (t, J=4.47 Hz, 2H), 4.26 (t, J=4.47 Hz, 2H), 3.41 (dd,J=14.11, 4.06 Hz, 1H), 3.10 (dd, J=14.11 9.36 Hz, 1H), 2.92 (t, J=7.63Hz, 2H), 2.24 (s, 3H), 1.90-1.60 (m, 2H), 1.05 (t, J=7.65 Hz, 3H).

EXAMPLE 185-[4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione ##STR103##

The title compound (850 mg, 85%) was obtained from5-[[2-[2,4-dimethyl-6-oxo-1,6-dihydro 1-pyrimidinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione (1.0 g) (obtained from example 2) by asimilar procedure to that described in example 17, mp 170° C.

¹ H NMR (CDCl₃): δ8.15 (bs, 1H, D₂ O exchangeable), 7.14 (d, J=8.30 Hz,2H), 6.80 (d, J=8.30, 2H), 6.21 (s, 1H), 4.50 (dd, J=9.13, 3.73 Hz, 1H),4.48-4.20 (n, 4H), 3.41 (dd, J=14.12, 3.73 Hz, 1H), 3.13 (dd, J=14.12,9.13 Hz, 1H), 2.70 (s, 3H), 2.25 (s, 3H).

EXAMPLE 195-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]thiazolidine2,4-dione ##STR104## Method A

The title compound (820 mg, 82%) was obtained from5-[4-[2-[2-ethyl-4-methyl-6-oxo1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione (1.0 g, 2.6 mmol) (obtained fromexample 3) by a similar procedure to that described in example 17.

Method B

To a stirred solution of5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro1-pyrimidinyl]ethoxy]phenylmethyl]-2-iminothiazolidine-4-one (1.93 g, 5.0 mmol) (obtained frompreparation 26) in ethanol (15 ml) was added 2N HCl (10 ml) and refluxedfor 12 h. The reaction mixture was cooled to room temperature andethanol was removed under reduced pressure. The aqueous layer wasneutralised with saturated aqueous NaHCO₃ solution and extracted withEtOAc (3×20 ml). The combined organic layer was washed with brine, driedover anhydrous Na₂ SO₄ and concentrated to yield the title compound(1.63 g, 84%) which was crystallised from CH₂ Cl₂ -pet. ether, mp 148°C. The title compound upon crystallisation from MeOH provided anotherpolymorph, mp 155° C.

¹ H NMR (CDCl₃) δ8.65 (bs, 1H, D₂ O exchangeable), 7.12 (d, J=8.51 Hz,2H), 6.79 (d, J=8.51 Hz, 2H), 6.21 (s, 1H), 4.43 (dd, J=9.27, 3.83 Hz,1H), 4.42 (t, J=4.57 Hz, 2H), 4.26 (t, J=4.57 Hz, 2H), 3.41 (dd,J=14.11, 3.83 Hz, 1H), 3.11 (dd, J=14.11, 9.27 Hz, 1H), 2.99 (q, J=7.47Hz, 2H), 2.25 (s, 3H), 1.34 (t, J=7.47 Hz, 3H).

EXAMPLE 205-[4-[2-[2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy] PhenylMethyl]thiazolidine-2,4-dione ##STR105##

The title compound (780 mg, 78%) was obtained from5-[4-[2-[2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione (1.0 g) (obtained from example 4) by asimilar procedure to that described in example 17, mp 150-152° C.

¹ H NMR (CDCl₃): δ9.53 (bs, 1H, D₂ O exchangeable), 7.13 (d, J=8.40 Hz,2H), 6.79 (d, J=8.40 Hz, 2H), 6.22 (s, 1H), 4.45 (dd, J=9.22, 3.83 Hz,1H), 4.42 (t, J=4.57 Hz, 2H), 4.26 (t, J=4.57 Hz, 2H), 3.42 (dd, J=14.12Hz, 3.83 Hz, 1H), 3.09 (dd, J=14.12, 9.22 Hz, 1H), 2.95 (t, J=7.47 Hz,2H), 2.24 (s, 3H), 1.85-1.65 (m, 2H), 1.58-1.32 (m, 2H), 0.98 (t, J=7.38Hz, 3H).

EXAMPLE 215-[4-[2-[2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione ##STR106##

The title compound (300 mg, 50%) was obtained from5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione (600 mg, 1.38 mmol) (obtained fromexample 7) by a similar procedure to that described in example 17, mp178° C.

¹ H NMR (CDCl₃): δ8.20-7.95 (m, 2H), 7.55-7.35 (m, 3H), 7.12 (d, J=8.30Hz, 2H), 6.80 (d, J=8.30 Hz, 2H), 6.80 (s, 1H), 4.60-4.40 (m, 3H),4.40-4.20 (m, 2H), 3.41 (dd, J=14.1, 3.65 Hz, 1H), 3.09 (dd and qoverlap, 3H), 1.46 (t, J=7.30 Hz, 3H).

EXAMPLE 225-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylMethyl]thiazolidine-2,4-dione ##STR107## Method A

The title compound (750 mg, 75%) was obtained from5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethylene]thiazolidine-2,4-dione (1.0 g) (obtained from example 12) by asimilar procedure to that described in example 17.

Method B

To a stirred solution of[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (1.9 g,6.75 mmol) (obtained form preparation 38) in dichloromethane (15 ml) wasadded triethyl amine (1.876 ml, 1.36 g, 13.48 mmol) followed by pivaloylchloride (0.913 ml, 899 mg, 5.46 mmol) at 0° C. and stirring wascontinued for 1 h at 0° C. The above reaction mixture was added to asolution of 2-amino-N-methyl benzamide (920 mg, 6.13 mmol) in aceticacid (20 ml) and refluxed for 24 h. The reaction mixture was cooled toroom temperature and acetic acid was removed under reduced pressure. Tothe residue water (50 ml) was added and extracted with CHCl₃ (3×25 ml).The combined CHCl₃ extracts were washed with brine, dried over anhydrousNa₂ SO₄ and concentrated to yield the title compound (2.16 g, 81% ), mp190° C.

Method C

To a stirred solution of[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (33 g,0.117 mol) in dichloromethane (300 mL) was added triethyl amine (35.4mL, 0.254 mol) followed by pivaloyl chloride (17.3 mL, 0.127 mol) at 0°C. and stirred for 1 h at 0° C. The reaction mixture was added to asolution of 2-amino-N-methyl benzamide (16 g, 0.106 mol) in a mixture ofacetic acid (300 mL) and xylene (300 mL) and refluxed for 18 h. Thereaction mixture was cooled to room temperature and solvents wereremoved under reduced pressure. The product was purified to yield thetitle compound (35.5 g, 85%).

Method D

To a stirred solution of[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (1.9 g,6.75 mmol) in dichloromethane (15 mL) was added triethy lamine (1.876mL, 1.36 g, 13.48 mmol) followed by pivaloyl chloride (0.913 mL, 899 mg,5.46 mmol) at 0° C. and stirring was continued for 1 h at 0° C. Theabove reaction mixture was added to a solution of 2-amino-N-methylbenzamide (920 mg, 6.13 mmol) in xylene (20 mL) containing pTsOH.H₂ O(646 mg, 3.4 mmol) and refluxed for 24 h. The reaction mixture wascooled to room temperature and xylene was removed under reducedpressure. Water (50 mL) was added to the residue and extracted withCHCl₃ (3×25 mL). The combined CHCl₃ extracts were washed with brine,dried over anhydrous Na₂ SO₄ and concentrated to yield the titlecompound (1.79 g, 58%).

Method E

To a stirred solution of[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (1.0 g,3.56 mmol) in xylene (10 mL) was added thionyl chloride (1,6 mL, 2.12 g,17.8 mmol) and refluxed for 1 h. The reaction mixture was cooled to 25°C. and excess thionyl chloride was removed and then was added to asolution of 2-amino-N-methyl benzamide (534 mg, 3.56 mmol) in a mixtureof acetic acid (10 mL) and xylene (5 mL) and refluxed for 20 h. Thereaction mixture was cooled to room temperature and the solvents wereremoved under reduced pressure. To the residue water (20 mL) was addedand extracted with CHCl₃ (3×25 mL). The combined CHCl₃ extracts werewashed with brine, dried over anhydrous Na₂ SO₄ and concentrated toyield the title compound (750 mg, 54%).

Method F

[5-[[4-[N-Methyl benzamide-2-yl]aminocarbonyl]methoxy]phenylmethyl]thiazolidine2,4-dione (1.0 g) (obtained in preparation 39) washeated at 180° C. for 8 h. The reaction mixture was cooled to roomtemperature diluted with water and extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated.

Method G

The title compound (345 mg, 34%) was prepared from5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethylene]thiazolidine-2,4-dione (1.0 g) (obtained from example 12) by asimilar procedure to that described in preparation 37, method B.

Polymorphs

Polymorph I

5-[4-[[3-[methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione (10 g) obtained from any one of the abovemethods was dissolved in dioxane (200 mL) by warming upto 60° C. Thesolution was concentrated to 30-50 ml to which methanol was added andstirred for 15-30 min. The white solid precipitated out was filtered anddried to yield the polymorph I, which is having DSC endotherm at 198° C.

Polymorph II

5-[4[-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]mehoxy]phenylmethyl]thiazolidine-2,4-dione (10 g) obtained from any one of themethods, was dissolved in acetone (300 mL). The solution wasconcentrated to 30-50 ml and methanol was added. After stirring for15-30 min, the precipitated white solid was filtered and dried to yieldthe polymorph II, which is having DSC endotherm at 180° C.

¹ H NMR (CDCl₃): δ8.70 (bs, 1H, D₂ O exchangeable), 8.31 (d, J=7.89 Hz,1H), 7.88-7.68 (m, 2H), 7.60-7.45 (m, 1H), 7.19 (d, J=8.46 Hz, 2H), 7.02(d, J=8.46 Hz, 2H), 5.18 (s, 2H), 4.50 (dd, J=9.22, 3.90 Hz, 1H), 3.75(s, 3H), 3.45 (dd, J=14.11, 3.90 Hz, 1H), 3.13 (dd, J 14.11, 9.22Hz,1H).

EXAMPLE 23 5-[4-[[3-Ethyl-4Oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylMethyl]thiazolidine-2,4-dione ##STR108## Method A

The title compound (1.186 g, 58%) was obtained from5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylMethylene]thiazolidine-2,4-dione (2.035 g, 5.0 mmol) (obtained fromexample 13) by a similar procedure to that described in example 17.

Method B

The title compound (278 mg, 68%) was obtained from4-[[2,4-2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (281mg, 1.0 mmol) (obtained from preparation 38) and 2-amino-N-methylbenzamide (164 mg, 1.0 mmol) by a similar procedure to that described inexample 22 in method B. mp=218° C.

¹ H NMR (CDCl₃): δ9.20 (bs, 1H, D₂ O exchangeable) 8.30 (d, J=7.84 Hz,1H), 7.84-7.64 (m, 2H), 7.60-7.48 (m, 1H), 7.19 (d, J=8.46 Hz, 2H), 7.02(d, J=8.46 Hz, 2H), 5.25 (s, 2H)., 4.51 (dd, J=9.30, 3.95 Hz, 1H), 3.94(q, J=6.92 Hz, 2H), 3.42 (dd, J=14.12, 3.95 Hz, 1H), 3.11 (dd, J=14.2,9.30 Hz, 1H), 1.35 (t, J=6.92 Hz, 3H).

EXAMPLE 245-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione ##STR109##

The title compound (173 mg, 82%) was obtained from5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]-2-iminothiazolidine-4-one (211 mg, 0.5 mmol) (obtained frompreparation 27) by a similar procedure to that described in example 19(Method B), mp 178-180° C.

¹ H NMR (CDCl₃): δ8.24 (d, J=7.88 Hz, 1H), 7.80-7.60 (m, 2H), 7.43 (t,J=7.56 Hz, 1H), 7.10 (d, J=8.63 Hz, 2H), 6.80 (d, J=8.63 Hz, 2H), 4.54(t, J=5.03 Hz, 2H), 4.46 (dd, J=9.22, 3.83 Hz, 1H), 4.32 (t, J=5.03 Hz,2H), 3.40 (dd, J=14.35, 3.83 Hz, 1H), 3.20-2.90 (m, 3H), 1.43 (t, J=7.48Hz, 3H).

EXAMPLE 252-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]-1,2,4-oxadiazolidine-3,5-dione ##STR110## Method A

To a stirred solution ofN-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl]-N-hydroxyurea(346 mg, 1.0 mmol) (obtained from preparation 19) in water (2 ml) wasadded IN NaOH (3 ml) followed by ethyl chloroformate (191 μl, 217 mg,2.0 mmol) and stirred for 1 h at 30° C. The reaction mixture was dilutedwith water, acidified to pH 3.0 and extracted with EtOAc (3×10 ml). Thecombined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated to yield the title compound (283 mg, 76%).

Method B

To a cold (-5° C.) solution of4-[2-[2-ethyl-4-methyl-6-oxo-1,4-dihydro-1-pyrimidinyl]ethoxy]benzylhydroxylamine (304 mg, 1.0 mmol) (obtained from preparation 18) inanhydrous THF (4.0 ml) was added N-(chlorocarbonyl)isocyanate (88 μl,116 mg, 1.1 mmol) dropwise. The mixture was stirred for 30 min. andpoured into 2N HCl followed by extraction with EtOAc (3×10 ml). Thecombined organic extracts were washed with brine, dried over anhydrousNa₂ SO₄ and concentrated to yield the title compound (264 mg, 71%). ¹ HNMR (CDCl₃ +DMSO-d₆): δ12.40 (bs, 1H, D₂ O exchangeable), 7.25 (d,J=8.72 Hz, 2H), 6.90 (d, J=8.72 Hz, 2H), 6.15 (s, 1H), 4.70 (s, 2H),4.40-4.25 (m, 2H), 4.25-4.12 (m,2H), 2.91 (q, J=7.56 Hz, 2H), 2.12 (s,3H), 1.20 (t, J=7.56 Hz, 3H).

EXAMPLE 265-[4-[2-2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethylene]oxazolidine-2,4-dione ##STR111##

To a stirred solution of5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethylene]-2-thio-1,3-oxazolidine-one (100 mg, 0.259 mmol) (obtainedfrom preparation 30) in dry DMF (2 ml) was added 3-chloroperbenzoic acid(179 mg, 0.68 mmol 65%) at 0° C. and stirred for 30 min at 0° C. to 10°C. and then at 30° C. for 5 h. The reaction mixture was diluted withethyl acetate (10 ml), washed with water (5 ml) and then with brine (5ml); dried over anhydrous Na₂ SO₄ and concentrated. The crude productwas purified by flash chromatography to yield the title compound (72 mg,75%).

¹ H NMR (CDCl₃ +DMSO-d₆): δ7.68 (d, J=8.72 Hz, 2H), 6.91 (d, J=8.72 Hz,2H), 6.61 (s, 1H), 6.16 (s, 1H), 4.50-4.38 (m, 2H), 4.38-4.00 (m, 2H),3.12 (q, J=7.47 Hz, 2H), 2.24 (s, 3H), 1.35 (t, J=7.47 Hz, 3H).

EXAMPLE 275-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]oxazolidine-2,4-dione ##STR112## Method A

A solution of5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethylene]oxazolidine-2,4-dione (100 mg) (obtained from example 26) in1,4-dioxane (10 ml) was reduced with hydrogen in the presence of 10%palladium on charcoal (20 mg) at 50 psi for 24 h. The mixture wasfiltered through a bed of celite. The filtrate was evaporated to drynessunder reduced pressure, purified by column chromatography (2:1EtOAc/petroleum ether as eluent) to afford the title compound (90 mg,90%).

Method B

A solution of ethyl3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]-2-hydroxypropanoate (93 mg, 0.25 mmol) (obtained from preparation 29), urea (30mg, 0.5 mmol) and sodium methoxide (22 mg, 0.4 mmol) in a mixture ofmethanol (0.5 ml) and ethanol (2.0 ml) was stirred for 2 h at 30° C.,followed by reflux for 2 h. The reaction mixture was cooled to roomtemperature and acidified with 2N HCl to pH 4 and extracted with ethylacetate (2×10 ml). The combined organic extracts were washed with water(5 mL), brine (5 mL), dried over anhydrous Na₂ SO₄ and concentrated toyield the title compound (35 mg, 38%).

¹ H NMR (CDCl₃ +DMSO-d₆): δ7.14 (d, J=8.51 Hz, 2H), 6.77 (d, J=8.5 Hz,2H), 6.17 (s, 1H), 4.95 (t, J=4.82 Hz, 1H), 4.42 (t, J=4.94 Hz, 2H),4.24 (t, J=4.94 Hz, 2H), 3.38-3.00 (m, 2H), 3.00 (q, J=7.42 Hz, 2H),2.25 (s, 3H), 1.34 (t, J=7.42 Hz, 3H).

EXAMPLE 285-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylMethyl]thiazolidine-2,4-dione Sodium Salt ##STR113##

To a stirred suspension of5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione (21.0 g, 53.2 mmol) (obtained from example22) in methanol (200 ml) was added a solution of sodium methoxide (11.45g, 212 mmol) in methanol (25 ml) dropwise at 30° C. During this periodthe suspension slowly dissolved completely and a white solidprecipitated out which was stirred further for 1 h. The solid wasfiltered and washed with methanol (20 ml) and dried to afford the titlecompound (20.6 g, 93%), mp 235° C.

¹ H NMR (DMSO-d₆): δ8.16 (d, J=7.47 Hz, 1H), 7.84 (t, J=7.47 Hz, I1H),7.69 (d, J=7.47 Hz, 1H), 7.56 (t, J=7.47 Hz, 1H), 7.15 (d, J=8.72 Hz,2H), 7.00 (d, J=8.72 Hz, 2H), 5.25 (s, 2H), 4.09 (dd, J=10.34, 3.36 Hz,1H), 3.61 (s, 3H), 3.30 (dd, J=13.82, 3.36 Hz, 1H), 2.62 (dd, J=13.82,10.34 Hz, 1H).

Polymorphs

The reactions were carried out in variety of solvents, using differentequivalents of base and different amounts of solvents.

Different polymorphs were observed depending on conditions used, whichhas shown in the following table:

    ______________________________________                                                 CONDITIONS                                                           S.             Free              eq.    DSC                                     No.        Polymorphs            Acid   Solvent/mL          of NaOMe                                                 endotherm                            ______________________________________                                        1.   Form I    1 g    Isopropanol-10 mL                                                                        1.5 eq 280° C.                          2.      Form II           1 g   Methanol-15 mL    2.0 eq                                                            276° C.                          3.  Form III     1 g   Methanol-10 mL    2.0 eq          272° C.       4.  Form IV           1 g   Ether-5 mL        1.5 eq          263.degree                                            . C.                                    5.  Form V            1 g   Ethanol-10 mL     1.1 eq          185.degree                                            . C.                                  ______________________________________                                    

EXAMPLE 295-[4-[2-[2,5,6-Trimethyl-4-oxo-3,4-dihydro-thieno-[2,3-d]-pyrimidin-3-yl]ethoxy]phenylMethylene]thiazolidine-2,4,-dione ##STR114##

The title compound (550 mg, 85%) was obtained from4-[2-[2,5,6-trimethyl-4-oxo-thieno-3-pyrimidinyl]ethoxy]benzaldehyde(500 mg, 1.46 mmol) (obtained from preparation 31) andthiazolidine-2,4-dione (257 mg, 2.2 mmol) by a similar procedure to thatdescribed in example 1, mp 280° C.

¹ H NMR (DMSO-d₆): δ12.52 (bs, 1H, D₂ O exchangeable), 7.71 (s, 1H),7.52 (d, J=8.39 Hz, 2H), 7.10 (d, J=8.39 Hz, 2H), 4.50-4.20 (m, 4H),2.66 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H).

EXAMPLE 305-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethylene]thiazolidine-2,4-dione, Sodium Salt ##STR115##

The title compound (385 mg, 90%) was obtained from5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione (obtained from example 9) (407 mg, 1.0mmol) by a similar procedure to that described in example 28. mp 280° C.(decomposes)

¹ H NMR (DMSO-d₆ +CDCl₃): δ8.12 (d, J=8.0 Hz, 1H), 7.78 (t, J=8.0 Hz,1H), 7.58 (d, J=8.0 Hz, 1H), 7.46 (t, J 8.0 Hz, 1), 7.45 (d, J=8.7 Hz,2), 7.25 (s, 1), 6.98 (d, =8.7 Hz, 2H), 4.55-4.40 (m, 2H), 4.40-4.25 (m,2H), 2.75 (s, 3H).

EXAMPLE 315-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethylene] Thiazolidine-2,4-dione, Sodium Salt ##STR116##

The title compound (405 mg, 91%) was obtained fromS-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione (obtained from example 10) (421 mg, 1.0mmol), by a similar procedure to that described in example 28. mp: 250°C. (decomposes).

¹ H NMR (DMSO-d₆ +CDCl₃): δ8.15 (d, J=8.0 Hz, 1H), 7.79 (t, J=8.0 Hz,1H), 7.65 (s, 1H), 7.60-7.45 (m, 4H), 7.10 (d, J=8.7 Hz, 2H), 4.60-4.45(m, 2H), 4.45-4.32 (m, 2H), 3.10 (q, J=7.5 Hz, 2H), 1.35 (t, J=7.5 Hz,3H).

EXAMPLE 325-[4-[2-[4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione, Sodium Salt ##STR117##

The title compound (460 mg, 88.5%) was obtained from5-[4-[2-[2-ethyl-2-propyl-6-oxo-1,6 dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione (obtained from example 17) (560 mg, 1.21mmol) by a similar procedure to that described in example 28, mp : 230°C.

¹ H NMR (DMSO-d₆): δ7.09 (d, J=8.53 Hz, 2H), 6.78 (d, J=8.53 Hz, 2H),6.15 (s, 1H), 4.38-4.25 (m, 2H), 4.25-4.10 (m, 2H), 4.06 (dd, J=10.47,3.42 Hz, 1H), 3.28 (dd, J=13.69, 10.47 Hz, 1H), 2.85 (t, J=7.4 Hz, 2H),2.62 (dd, J=13.69, 3.42 Hz, 1H), 2.15 (s, 3H), 1.71 (q, J=7.47 Hz, 2H),0.96 (t, J=7.47 Hz, 3H).

EXAMPLE 335-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione, Sodium Salt ##STR118##

The title compound (0.6 g, 94.6%) was obtained from5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione (0.6 g, 1.55 mmol) (obtained from example19) by a similar procedure to that described in example 28. mp :258-260° C.

¹ H NMR (DMSO-d₆): δ7.10 (d, J=7.53 Hz, 2H), 6.80 (d, J=7.53 Hz, 2H),6.16 (s, 1H), 4.32 (t, J=5.26 Hz, 2H), 4.16 (t, J=5.26 Hz, 2H), 4.10(dd, J=9.6, 3,4 Hz, 1H), 3.4-3.25 (dd, J=13.6, 9.62 Hz, 1H), 2.91 (q,J=7.3 Hz, 2H), 2.59 (dd, J=13.6, 3,4 Hz, 1H), 2.66 (s, 3H), 1.25 (t,J=7.3 Hz, 3H).

EXAMPLE 345-[4-[2-[2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione ##STR119##

The title compound (550 mg) was obtained from[4-[2-[2-ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde(700 mg, 2.05 mmol) (obtained from preparation 36) andthiazolidine-2,4-dione (240 mg, 2.05 mmol) by a similar procedure tothat described in example 1. mp: >250° C.

¹ H NMR (CDCl₃ +DMSO-d₆): 5 7.70 (s, 1H), 7.45 (d, J=8.3 Hz, 2H), 6.95(d, J=8.3 Hz, 2H), 6.69 (s, 1H), 4.50 (t, J=4.5 Hz, 2H), 4.35 (t, J=4.5Hz, 2H), 3.11 (q, J=7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).

EXAMPLE 355-[4-[2-[2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione ##STR120##

The title compound (0.3 g, 66%) was obtained from5-[4-[2-[2-ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione (0.45 g, 1.025 mmol) obtained from example34 by a similar procedure to that described in example 17. p: 135° C.

¹ H NMR (DMSO-d₆): δ7.11 (d, J 8.53 Hz, 2H), 6.77 (d, J=8.53 Hz, 2H),6.70 (s, 1H), 4.52-4.38 (m, 1H), 4.46 (t, =4.68 Hz, 2H), 4.28 (t, =4.68Hz, 2H), 3,4 (dd, J=14.21, 3.83 Hz, 1H), 3.20-2.98 (m, 3H), 1.38 (t,J=7.33 Hz, 3H).

EXAMPLE 365-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione ##STR121##

The title compound (1.6 g, 89%) was obtained from5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]-2-iminothiazolidine-4-one (1.8g, 4.4 mmol) (obtained frompreparation 35) by a similar procedure to that described in example 19(method B), 242-2444° C.

¹ H NMR (DMSO-d₆): δ11.98 (bs, 1H, D₂ O exchangeable), 8.11 (d, J=7.50Hz, 1H), 7.80 (t, J=7.50 Hz, 1H), 7.59 (d, J=7.50 Hz, 1H), 7.48 (t,J=7.50 Hz, 1H), 7.14 (d, J=8.35 Hz, 2H), 6.89 (d, J=8.35 Hz, 2H), 4.85(dd, J=9.03, 4.20 Hz, 1H), 4.45 (t, J=5.14 Hz, 2H), 4.27 (t, J=5.14 Hz,2H), 3.28 (dd, J=14.12, 4.20 Hz, 1H), 3.04 (dd, J=14.12, 9.03 Hz, 1H),2.71 (s, 3H).

EXAMPLE 375-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione, Sodium Salt ##STR122##

The title compound (348 mg, 81%) was obtained from5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]thiazolidine2,4-dione (409 mg, 1 mmol) (obtained from example 36)by a similar procedure to that described in example 28. mp: 317° C.

¹ H NMR (DMSO-d₆) 8 8.11 (d, J=7.88 Hz, 1H), 7.79 (t, J=7.05 Hz, 1H),7.59 (d, J=7.88 Hz, 1H), 7.48 (t, J=7.05 Hz, 1H), 7.08 (d, J=8.40 Hz,2H), 6.83 (d, J=8.40 Hz, 2H), 4.44 (t, J=5.40 Hz, 2H), 4.26 (t, J=5.40Hz, 2H), 4.06 (dd, J=10.43, 3.42 Hz, 1H), 3.28 (dd, J=13.8, 3.42 Hz,1H), 2.62 (dd, J=13.8, 10.43 Hz, 1H), 2.71 (s, 3H).

EXAMPLE 385-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylMethyl]thiazolidine-2,4-dione, Sodium Salt ##STR123##

The title compound (700 mg, 68%) was obtained from5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione (978 mg, 2.3 mmol) (obtained from example24) by a similar procedure to that described in example 28. mp: 280° C.

¹ H NMR (DMSO-d₆) δ: 8.15 (d, J=7.89 Hz, 1H), 7.82 (t, J=7.89 Hz, 1H),7.65 (d, J=7.89 Hz, 1H), 7.51 (t, J=7.89 Hz, 1H), 7.11 (d, J=8.40 Hz,2H), 6.83 (d, J=8.40 Hz, 2H), 4.48 (t, J=5.4 Hz, 2H), 4.27 (t, J=5.40Hz, 2H), 4.08 (dd, J=10.39, 3.12 Hz, 1H), 3.25 (dd, J=10.39, 3.12 Hz,1H), 3.06 (q, J=7.15 Hz, 2H), 2.64 (dd, J=13.82, 10.39 Hz, 1H), 1.34 (t,J=7.15 Hz, 3H).

EXAMPLE 395-[4-[[6,7-Dimethoxy-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylMethyl]thiazolidine-2,4-dione ##STR124##

The title compound (1.0 g, 44%) was obtained from4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (1.05 g,5.0 mmol) 2-amino-N-methyl benzamide (1.5 g, 5.34 mmol) by a similarprocedure to that described in example 22, method B; mp: 252° C.

¹ H NMR (CDCl₃): δ7.61 (s, 1H), 7.46 (s, 1H), 7.14 (d, J=8.72 Hz, 2H),6.98 (d, J=8.72 Hz, 2H), 5.15 (s, 2H), 4.5 (dd, J=10.20, 3.30 Hz, 1H),4.0 (s, 6H), 3.74 (s, 3H), 3.45 (dd, J=14.3 , 3.30 Hz, 1H), 3.16 (dd,J=14.3, 10.20 Hz, 1H).

EXAMPLE 405-[4-[[6,7-Dimethoxy-3-methyl-4-oxo-3,4-dihydro-2quinazolinyl]methoxy]phenylMethyl]thiazolidine-2,4-dione, Sodium Salt ##STR125##

The title compound (140 mg, 64%) was obtained from5-[4-[[(6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione (210 mg, 0.46 mmol) (obtained from example39) by a similar procedure to that described in example 28. mp : 275° C.

¹ H NMR (DMSO-d₆): δ7.46 (s, 1H), 7.16 (s, 1H), 7.14 (d, J=7.50 Hz, 2H),6.98 (d, J=7.50 Hz, 2H), 5.19 (s, 2H), 4.20 (dd, J=10.50, 3.50 Hz, 1H),3.90 (5, 3H), 3.88 (5, 3H), 3.60 (s, 3H), 3.32 (dd, J=13.70 Hz, 3.50 Hz,1H), 2.67 (dd, J=13.7, 10.0 Hz, 1H).

EXAMPLE 415-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylMethyl]thiazolidine-2,4-dione, Potassium Salt ##STR126##

To a stirred solution of5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione (10.0 g, 25.3 mmol) (obtained from example22) in methanol (100 mL) was added a solution of tBuOK (3.40 g, 30.3mmol) in methanol (50 mL) dropwise at 30° C. During this period thesuspension slowly dissolved completely and a white solid precipitatedout which was stirred further for 1 h. The solid was filtered and washedwith methanol (20 mL) and dried to afford the title compound (9.8 g,90%). mp: 302° C.

¹ H N (DMSO-d₆): δ8.17 (d, J=7.89 Hz, 1H), 7.85 (t, J=7.52 Hz, 1H), 7.7(d, J=7.89 Hz, 1H), 7.58 (t, J=7.52 Hz, 1H), 7.16 (d, J=8.63 Hz,2H),7.01 (d, J=8.63 Hz, 2H), 5.25 (s, 2H), 4.12 (dd, J=10.47, 3.56 Hz,1H), 3.62 (s, 3H), 3.32 (dd, J=13.70, 3.56 Hz, 1H), 2.65 (dd, J=13.70,10.47 Hz, 1H).

EXAMPLE 425-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione, Calcium Salt ##STR127##

A mixture of5-[4-[[3-[methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl]methyl]thiazolidine-2,4-dione(1.0 g, 2.53 mmol) (obtained from example 22) and Ca(OH)₂ (94 mg, 1.27mmol) in methanol (40 mL) was immersed in preheated oil bath at 100° C.and refluxed for 4h. The reaction mixture was cooled to room temperatureand methanol was completely removed under reduced pressure at 40-50° C.The resultant foamy solid was triturated with ether. The whitecrystalline compound obtained was filtered and washed with ether (5-10mL) and dried to afford the title compound (1.025 g, 94%) mp : 225° C.

¹ H NMR (DMSO-d₆): 8 8.15 (d, J=7.89 Hz, 1H), 7.83 (t, J=7.89 Hz, 1H),7.68 (d, J=7.89 Hz, 1H), 7.56 (t, J=7.89 Hz, 1H), 7.16 (d, J=8.35 Hz,2H), 7.01 (d, J=8.35 Hz, 2H), 5.24 (s, 2H), 4.23 (dd, J=10.38, 3.23 Hz,1H), 3.61 (s, 3H), 3.33 (dd, J=13.70, 3.23 Hz, 1H), 2.70 (dd, J=13.7,10.38 Hz, 1H).

EXAMPLE 435-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethylene]thiazolidine-2,4-dione, Sodium Salt ##STR128##

The title compound (1.89 g, 90%) was obtained from5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethylene]thiazolidine-2,4-dione (2.0 g, 5.09 mmol) (obtained fromexample 12) by a similar procedure to that described in example 28. mp :299° C.

¹ H NMR (DMSO-d₆) δ: 8.18 (d, J=7.89 Hz, 1H), 7.86 (t, J=7.89 Hz, 1H),7.69 (d, J=7.89 Hz, 1H), 7.59 (t, J=7.89 Hz, 1H), 7.52 (d, J=8.72 Hz,2H), 7.28 (s, 1H), 7.21 (d, J=8.72 Hz, 2H), 5.35 (s, 2H), 3.64 (s, 3H).

Mutation in colonies of laboratory animals and different sensitivitiesto dietary regimens have made the development of animal models withnon-insulin dependent diabetes associated with obesity and insulinresistance possible. Genetic models such as db/db and ob/ob (SeeDiabetes, (1982) 31(1): 1-6) in mice and fa/fa and zucker rats have beendeveloped by the various laboratories for understanding thepathophysiology of disease and testing the efficacy of new antidiabeticcompounds (Diabetes, (1983) 32: 830-838; Annu. Rep. Sankyo Res. Lab.(1994) 46: 1-57). The homozygous animals, C57 BL/KsJ-db/db micedeveloped by Jackson Laboratory, US, are obese, hyperglycemic,hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85:962-967), whereas heterozygous are lean and normoglycemic. In db/dbmodel, mouse progressively develops insulinopenia with age, a featurecommonly observed in late stages of human type II diabetes when bloodsugar levels are insufficiently controlled The state of pancreas and itscourse vary according to the models. Since this model resembles that oftype II diabetes mellitus, the compounds of the present invention weretested for blood sugar and triglycerides lowering activities.

The compounds of the present invention showed blood sugar andtriglycerides lowering activites through improved insulin resistance.This was demonstrated by the following in vivo experiments.

Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight rangeof 35 to 60 grams, procured from the Jackson Laboraotory, USA, were usedin the experiment. The mice were provided with standard feed (NationalInstitute of Nutrition, Hyderabad, India) and acidified water, adlibitum. The animals having more than 300 mg/dl blood sugar were usedfor testing. The number of animals in each group was 4.

The random blood sugar and triglyceride levels were measured bycollecting blood (100 μl) through orbital sinus, using heparinisedcapillary in tubes containing EDTA which was centrifuged to obtainplasma. The plasma glucose and triglycerides levels were measuredspectrometrically, by glucose oxidase and glycerol-3-PO₄oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits,Hyderabad, India) methods respectively. On 6th day the blood sampleswere collected one hour after administration of test compounds/vehiclefor assessing the biological activity.

Test compounds were suspended on 0.25% carboxymethyl cellulose andadministered to test group at a dose of 10 mg to 100 mg/kg through oralgavage daily for 6 days. The control group received vehicle (dose 10ml/kg). Troglitazone (100 mg/kg, daily dose) was used as a standard drugwhich showed 28% reduction in random blood sugar level on 6th day.

The blood sugar and triglycerides lowering activities of the testcompound was calculated according to the formula: ##STR129## ZC=Zero daycontrol group value DC=Zero day treated group value

TC=Control group value on test day

DT=Treated group value on the test day

No adverse effects were observed for any of the mentioned compounds ofinvention in the above test.

The compounds of the present invention also showed cholesterol loweringactivity in the experimental animals used.

    ______________________________________                                                                 Maximum                                                   reduction in                                                                Dose Days blood glucose Triglyceride                                         Compound mg/kg/da treated level (%) lowering (%)                            ______________________________________                                        Example 3                                                                             100      6       67         12                                          Example 6 100 6 41 31                                                         Example 7 100 6 66 35                                                         Example 9  30 6 46 35                                                         Example 12 100 6 71 57                                                        Example 13 100 6 52 57                                                        Example 17  30 6 65 45                                                        Example 19  30 6 73 70                                                        Example 21  30 6 64 76                                                        Example 22  30 6 55 41                                                        Example 24  10 6 63 17                                                        Example 11  30 6 32 42                                                        Example 28  10 6 63 57                                                      ______________________________________                                    

The experimental results from the db/db mice suggest that the novelcompounds of the present invention also possess therapeutic utility as aprophylactic or regular treatment for obesity, cardiovascular disorderssuch as hypertension, hyperlipidaemia and other diseases; as it is knownfrom the literature that such diseases are interrelated to each other.

What is claimed is:
 1. A process for the preparation of compound offormula (I) ##STR130## where one of X, Y and Z represents C═O or C═S andone of the remaining of X, Y and Z represents a group C═ and the otherof the remaining X, Y and Z represents C═C; R¹, R² and R³ aresubstituents either on X, Y or Z or on a nitrogen atom and may be thesame or different and represent hydrogen, halogen, hydroxy or nitro, oroptionally substituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl,acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl,aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, thioalkyl, alkylthioor carboxylic acid or its derivatives or sulfonic acid or itsderivatives with the provision that when R¹, R² or R³ is on a nitrogenatom it does not represent hydrogen, halogen, nitro, carboxylic orsulfonic acid groups; or any two of R¹, R² and R³ along with theadjacent atoms to which they are attached may also form a substituted orunsubstituted cyclic structure of 4 to 7 atoms with one or more doublebonds, the cyclic structure may be carbocyclic or may contain one ormore heteroatoms selected from oxygen, nitrogen and sulfur; the linkinggroup represented by --(CH₂)_(n) --O-- may be attached either throughnitrogen or through X, Y or Z and n is an integer ranging from 1-4: Arrepresents an optionally substituted divalent aromatic or heterocyclicgroup; R⁴ represents hydrogen, halogen or lower alkyl group or forms abond together with the adjacent group A; A represents a nitrogen atom ora group CR⁵ where R⁵ represents hydrogen, halogen or lower alkyl groupor R⁵ forms a bond together with R⁴ ; B represents an oxygen or a sulfuratom when A is CR⁵ and B represents an oxygen atom when A is a nitrogenatom, comprising:a) reacting a compound of formula (XVII) ##STR131##where R¹, R² and R³ are as defined earlier, X represent, C═O or C═S andY represents C═C; or R² and R³ together with Y form a cyclic structureas defined earlier where X represents C═O or C═S, Y represents C═C andR¹ is as defined earlier, with a compound of formula (XVIII) ##STR132##where Ar, R⁴, A, B and n are as defined earlier, D is --CN or --C(OR⁷)₃where R⁷ is (C₁ -C₄)alkyl, or --C(═O)--R⁸ where R⁸ is selected from--OH, Cl, Br, I, --NH₂, --NHR, and OR where R is a lower alkyl group; orR⁸ is O--(C═O)--R₉, where R⁹ is a linear or branched (C₁ -C₅) alkylgroup and (b) converting a compound of formula (I) into itspharmaceutically acceptable salts, polymorphs, or solvates.
 2. A processaccording to claim 1 where the compound of formula (I) is formed throughthe intermediate formation of compound of formula (XIX), ##STR133##where R¹, R², R³, n, Ar, R⁴, A and B are as defined in claim 1 and Xrepresents C═O or C═S and Y represents C═C or Y together with R² and R³form a cyclic structure as defined in claim
 1. 3. A process according toclaim 2 wherein the intermediate of formula (XIX) ##STR134## where X, Y,R¹, R², R³, n, Ar, R⁴, A and B are as defined in claim 2 is cyclised toform the compound of formula (I).
 4. A process according to claim 1, toprepare a compound of formula (I) where X represents C═O, Y representsC═C, Z represents ═C, n represents the integer 1, R¹ represents methylgroup, B represents sulfur atom, R² and R³ together with Y form a phenylring and is represented by formula (XX) ##STR135## which comprises: a)reducing a compound of formula (XXI) ##STR136## where R¹⁰ is a loweralkyl group to yield a compound of formula (XXII) ##STR137## where R¹⁰is as defined above, b) hydrolysis of compound of formula (XXII) toyield a compound of formula (XXIII) ##STR138## c) reacting a compound offormula (XXIII) with acid halide or halogenating agent to obtain acompound of formula (XXIV) ##STR139## where D represents COCl, COBr or--C(═O)--O--(C═O)--R⁹, where R⁹ represents methyl or t-butyl group,d)reacting a compound of formula (XXIV) with a compound of formula (XXV)##STR140## to yield a compound of formula (XX) defined above through theintermediate formation of compound of formula (XXVI) and optionally##STR141## e) converting a compound of formula (XX) into itspharmaceutically acceptable salts, polymorphs, or solvates.
 5. A processaccording to claim 4, wherein the compound of formula (XXVI) ##STR142##is cyclised to obtain a compound of formula (XX) ##STR143##